Geneticist, Pediatrician
19 years of experience

Accepting new patients
Childrens Healthcare Associates Inc.
481 John Young Way
Exton, PA 19341
215-590-1024
Locations and availability (4)

Education ?

Medical School
Sackler School Of Medicine (1991)
Foreign school

Affiliations ?

Dr. Krantz is affiliated with 2 hospitals.

Hospital Affilations

Score

Rankings

  • Main Line Hospital - Bryn Mawr
    130 S Bryn Mawr Ave, Bryn Mawr, PA 19010
    • Currently 4 of 4 crosses
    Top 25%
  • Children's Hospital of Philadelphia
    324 S 34th St, Philadelphia, PA 19104
    • Currently 2 of 4 crosses
  • Publications & Research

    Dr. Krantz has contributed to 53 publications.
    Title Genome-wide Dna Methylation Analysis in Cohesin Mutant Human Cell Lines.
    Date October 2010
    Journal Nucleic Acids Research
    Excerpt

    The cohesin complex has recently been shown to be a key regulator of eukaryotic gene expression, although the mechanisms by which it exerts its effects are poorly understood. We have undertaken a genome-wide analysis of DNA methylation in cohesin-deficient cell lines from probands with Cornelia de Lange syndrome (CdLS). Heterozygous mutations in NIPBL, SMC1A and SMC3 genes account for ∼65% of individuals with CdLS. SMC1A and SMC3 are subunits of the cohesin complex that controls sister chromatid cohesion, whereas NIPBL facilitates cohesin loading and unloading. We have examined the methylation status of 27 578 CpG dinucleotides in 72 CdLS and control samples. We have documented the DNA methylation pattern in human lymphoblastoid cell lines (LCLs) as well as identified specific differential DNA methylation in CdLS. Subgroups of CdLS probands and controls can be classified using selected CpG loci. The X chromosome was also found to have a unique DNA methylation pattern in CdLS. Cohesin preferentially binds to hypo-methylated DNA in control LCLs, whereas the differential DNA methylation alters cohesin binding in CdLS. Our results suggest that in addition to DNA methylation multiple mechanisms may be involved in transcriptional regulation in human cells and in the resultant gene misexpression in CdLS.

    Title Facial Diagnosis of Mild and Variant Cdls: Insights from a Dysmorphologist Survey.
    Date September 2010
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Cornelia de Lange syndrome (CdLS) is a dominant disorder with classic severe forms and milder atypical variants. Central to making the diagnosis is identification of diagnostic facial features. With the recognition that patients with SMC1A and SMC3 mutations have milder, atypical features, we surveyed 65 dysmorphologists using facial photographs from 32 CdLS patients with the goals of (1) Illustrating examples of milder patients with SMC1A mutations and (2) Obtaining objective data to determine which facial features were useful and misleading in making a diagnosis of CdLS. Clinicians were surveyed whether the patient had CdLS or another diagnosis, the certainty of response and the clinical features used to support each response. Using only facial photographs, an average of 24 cases (75%) were accurately diagnosed per clinician. Correct diagnoses were made in 90% of classic CdLS and 87% of non-CdLS cases, however, only 54% of mild or variant CdLS were correctly diagnosed by respondents. We confirmed that CdLS is most accurately diagnosed in childhood and the diagnosis becomes increasingly difficult with age. This survey demonstrated that emphasis is placed on the eyebrows, nasal features, prominent upper lip and micrognathia. In addition, the presence of fuller, atypical eyebrows, a prominent nasal bridge and significant prognathism with age dissuaded survey takers from arriving at a diagnosis of CdLS in individuals with mild NIPBL and SMC1A mutations. This work underscores the difficulty in diagnosing patients with mild and variant CdLS and serves to objectively classify both useful and misleading features in the diagnosis of CdLS.

    Title Update on "two Siblings with Alternate Unbalanced Recombinants Derived from a Large Cryptic Maternal Pericentric Inversion of Chromosome 20".
    Date August 2010
    Journal American Journal of Medical Genetics. Part A
    Title Jagged1 (jag1) Mutations in Patients with Tetralogy of Fallot or Pulmonic Stenosis.
    Date July 2010
    Journal Human Mutation
    Excerpt

    Mutations in the Notch pathway ligand Jagged1 (JAG1) cause Alagille syndrome (AGS), as well as cardiac defects in seemingly nonsyndromic individuals. To estimate the frequency of JAG1 mutations in cases with right-sided cardiac defects not otherwise diagnosed with AGS, we screened 94 cases with tetralogy of Fallot (TOF) and 50 with pulmonic stenosis/peripheral pulmonary stenosis (PS/PPS) or pulmonary valve atresia with intact ventricular septum (PA) for mutations. Sequence changes were identified in three TOF and three PS/PPS/PA patients, that were not present in 100 controls. We identified one frameshift and two missense mutations in the TOF cases, and one frameshift and two missense mutations in cases with PS/PPS/PA. The four missense mutations were assayed for their effect on protein localization, posttranslational modification, and ability to activate Notch signaling. The missense mutants displayed heterogeneous behavior in these assays, some with complete haploinsufficiency, suggesting that there are additional modifiers leading to organ specific features. We identified functionally significant mutations in 2% (2/94) of TOF patients and 4% (2/50) of PS/PPS/PA patients. Patients with right-sided cardiac defects should be carefully screened for features of AGS or a family history of cardiac defects that might suggest the presence of a JAG1 mutation.

    Title Genomic Alterations in Biliary Atresia Suggest Region of Potential Disease Susceptibility in 2q37.3.
    Date July 2010
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Biliary atresia (BA) is a progressive, idiopathic obliteration of the extrahepatic biliary system occurring exclusively in the neonatal period. It is the most common disease leading to liver transplantation in children. The etiology of BA is unknown, although infectious, immune and genetic causes have been suggested. Although the recurrence of BA in families is not common, there are more than 30 multiplex families reported and an underlying genetic susceptibility has been hypothesized. We screened a cohort of 35 BA patients for genomic alterations that might confer susceptibility to BA. DNA was genotyped on the Illumina Human Hap 550 Beadchip platform, which analyzes over 550,000 single nucleotide polymorphisms (SNPs) for genomic deletions and duplications. Areas of increased and decreased copy number were compared to those found in control populations. To identify regions that could serve as susceptibility factors for BA, we searched for regions that were found in BA patients, but not in controls. We identified two unrelated BA patients with overlapping heterozygous deletions of 2q37.3. Patient 1 had a 1.76 Mb (280 SNP), heterozygous deletion containing 30 genes. Patient 2 had a 5.87 Mb (1,346 SNP) heterozygous deletion containing 55 genes. The overlapping 1.76 Mb deletion on chromosome 2q37.3 from 240,936,900 to 242,692,820 constitutes the critical region and the genes within this region could be candidates for susceptibility to BA.

    Title Consensus Statement: Chromosomal Microarray is a First-tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies.
    Date June 2010
    Journal American Journal of Human Genetics
    Excerpt

    Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%-20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype ( approximately 3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages.

    Title Mechanisms of Mosaicism, Chimerism and Uniparental Disomy Identified by Single Nucleotide Polymorphism Array Analysis.
    Date May 2010
    Journal Human Molecular Genetics
    Excerpt

    Mosaic aneuploidy and uniparental disomy (UPD) arise from mitotic or meiotic events. There are differences between these mechanisms in terms of (i) impact on embryonic development; (ii) co-occurrence of mosaic trisomy and UPD and (iii) potential recurrence risks. We used a genome-wide single nucleotide polymorphism (SNP) array to study patients with chromosome aneuploidy mosaicism, UPD and one individual with XX/XY chimerism to gain insight into the developmental mechanism and timing of these events. Sixteen cases of mosaic aneuploidy originated mitotically, and these included four rare trisomies and all of the monosomies, consistent with the influence of selective factors. Five trisomies arose meiotically, and three of the five had UPD in the disomic cells, confirming increased risk for UPD in the case of meiotic non-disjunction. Evidence for the meiotic origin of aneuploidy and UPD was seen in the patterns of recombination visible during analysis with 1-3 crossovers per chromosome. The mechanisms of formation of the UPD included trisomy rescue, with and without concomitant trisomy, monosomy rescue, and mitotic formation of a mosaic segmental UPD. UPD was also identified in an XX/XY chimeric individual, with one cell line having complete maternal UPD consistent with a parthenogenetic origin. Utilization of SNP arrays allows simultaneous evaluation of genomic alterations and insights into aneuploidy and UPD mechanisms. Differentiation of mitotic and meiotic origins for aneuploidy and UPD supports existence of selective factors against full trisomy of some chromosomes in the early embryo and provides data for estimation of recurrence and disease mechanisms.

    Title Two Siblings with Alternate Unbalanced Recombinants Derived from a Large Cryptic Maternal Pericentric Inversion of Chromosome 20.
    Date April 2010
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Two brothers, with dissimilar clinical features, were each found to have different abnormalities of chromosome 20 by subtelomere fluorescence in situ hybridization (FISH). The proband had deletion of 20p subtelomere and duplication of 20q subtelomere, while his brother was found to have a duplication of 20p subtelomere and deletion of 20q subtelomere. Parental cytogenetic studies were initially thought to be normal, both by G-banding and by subtelomere FISH analysis. Since chromosome 20 is a metacentric chromosome and an inversion was suspected, we used anchored FISH to assist in identifying a possible inversion. This approach employed concomitant hybridization of a FISH probe to the short (p) arm of chromosome 20 with the 20q subtelomere probe. We identified a cytogenetically non-visible, mosaic pericentric inversion of one of the maternal chromosome 20 homologs, providing a mechanistic explanation for the chromosomal abnormalities present in these brothers. Array comparative genomic hybridization (CGH) with both a custom-made BAC and cosmid-based subtelomere specific array (TEL array) and a commercially available SNP-based array confirmed and further characterized these rearrangements, identifying this as the largest pericentric inversion of chromosome 20 described to date. TEL array data indicate that the 20p breakpoint is defined by BAC RP11-978M13, approximately 900 kb from the pter; SNP array data reveal this breakpoint to occur within BAC RP11-978M13. The 20q breakpoint is defined by BAC RP11-93B14, approximately 1.7 Mb from the qter, by TEL array; SNP array data refine this breakpoint to within a gap between BACs on the TEL array (i.e., between RP11-93B14 and proximal BAC RP11-765G16).

    Title Smc1a Expression and Mechanism of Pathogenicity in Probands with X-linked Cornelia De Lange Syndrome.
    Date February 2010
    Journal Human Mutation
    Excerpt

    Cornelia de Lange Syndrome (CdLS) is a dominantly inherited heterogeneous genetic disorder with multisystem abnormalities. Sixty percent of probands with CdLS have heterozygous mutations in the Nipped-B-like (NIPBL) gene, 5% have mutations in the SMC1A gene, and one proband was found to have a mutation in the SMC3 gene. Cohesin is a multisubunit complex consisting of a SMC1A and SMC3 heterodimer and two non-SMC subunits. SMC1A is located on the human X chromosome and is reported to escape X inactivation. Twenty-nine unrelated CdLS probands with 21 unique SMC1A mutations have been identified including seven males. All mutations identified to date are either missense or small deletions, with all presumably preserving the protein open reading frame. Both wild-type and mutant alleles are expressed. Females quantitatively express twice the amount of SMC1A mRNA compared to males. The transcriptional profiling of 23 selected genes is different in SMC1A mutant probands, controls, and NIPBL mutant probands. These results suggest that mechanistically SMC1A-related CdLS is not due to altered levels of the SMC1A transcript, but rather that the mutant proteins maintain a residual function in males and enact a dominant negative effect in females.

    Title Microduplications of 16p11.2 Are Associated with Schizophrenia.
    Date November 2009
    Journal Nature Genetics
    Excerpt

    Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

    Title Transcriptional Dysregulation in Nipbl and Cohesin Mutant Human Cells.
    Date August 2009
    Journal Plos Biology
    Excerpt

    Cohesin regulates sister chromatid cohesion during the mitotic cell cycle with Nipped-B-Like (NIPBL) facilitating its loading and unloading. In addition to this canonical role, cohesin has also been demonstrated to play a critical role in regulation of gene expression in nondividing cells. Heterozygous mutations in the cohesin regulator NIPBL or cohesin structural components SMC1A and SMC3 result in the multisystem developmental disorder Cornelia de Lange Syndrome (CdLS). Genome-wide assessment of transcription in 16 mutant cell lines from severely affected CdLS probands has identified a unique profile of dysregulated gene expression that was validated in an additional 101 samples and correlates with phenotypic severity. This profile could serve as a diagnostic and classification tool. Cohesin binding analysis demonstrates a preference for intergenic regions suggesting a cis-regulatory function mimicking that of a boundary/insulator interacting protein. However, the binding sites are enriched within the promoter regions of the dysregulated genes and are significantly decreased in CdLS proband, indicating an alternative role of cohesin as a transcription factor.

    Title Mutations in the Chromatin-associated Protein Atrx.
    Date July 2008
    Journal Human Mutation
    Excerpt

    ATRX belongs to the SNF2 family of proteins, many of which have been demonstrated to have chromatin remodeling activity. Constitution mutations in the X-encoded gene give rise to alpha thalassemia mental retardation (ATR-X) syndrome and a variety of related conditions that are often associated with profound developmental delay, facial dysmorphism, genital abnormalities, and alpha thalassemia. Acquired mutations in ATRX are observed in the preleukemic condition alpha thalassemia myelodysplastic syndrome (ATMDS). Mutations in ATRX have been shown to perturb gene expression and DNA methylation. This is a comprehensive report of 127 mutations including 32 reported here for the first time. Missense mutations are shown to cluster in the two main functional domains. The truncating mutations appear to be "rescued" to some degree and so it appears likely that most if not all constitutional ATRX mutations are hypomorphs.

    Title Fine-mapping Subtelomeric Deletions and Duplications by Comparative Genomic Hybridization in 42 Individuals.
    Date April 2008
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Human subtelomere regions contain numerous gene-rich segments and are susceptible to germline rearrangements. The availability of diagnostic test kits to detect subtelomeric rearrangements has resulted in the diagnosis of numerous abnormalities with clinical implications including congenital heart abnormalities and mental retardation. Several of these have been described as clinically recognizable syndromes (e.g., deletion of 1p, 3p, 5q, 6p, 9q, and 22q). Given this, fine-mapping of subtelomeric breakpoints is of increasing importance to the assessment of genotype-phenotype correlations in these recognized syndromes as well as to the identification of additional syndromes. We developed a BAC and cosmid-based DNA array (TEL array) with high-resolution coverage of 10 Mb-sized subtelomeric regions, and used it to analyze 42 samples from unrelated patients with subtelomeric rearrangements whose breakpoints were previously either unmapped or mapped at a lower resolution than that achievable with the TEL array. Six apparently recurrent subtelomeric breakpoint loci were localized to genomic regions containing segmental duplication, copy number variation, and sequence gaps. Small (1 Mb or less) candidate gene regions for clinical phenotypes in separate patients were identified for 3p, 6q, 9q, and 10p deletions as well as for a 19q duplication. In addition to fine-mapping nearly all of the expected breakpoints, several previously unidentified rearrangements were detected.

    Title Bile Duct Anomalies in a Male Child with Noonan Syndrome: a Case for Ras and Notch Pathway Synergism.
    Date February 2008
    Journal American Journal of Medical Genetics. Part A
    Title Cornelia De Lange Syndrome: Clinical Review, Diagnostic and Scoring Systems, and Anticipatory Guidance.
    Date January 2008
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Cornelia de Lange syndrome (CdLS), also known as Brachmann-de Lange syndrome, is a well-described multiple malformation syndrome typically involving proportionate small stature, developmental delay, specific facial features, major malformations (particularly the cardiac, gastrointestinal and musculoskeletal systems), and behavioral abnormalities. There is a broad spectrum of clinical involvement, with increasing recognition of a much milder phenotype than previously recognized. Significant progress has been made in recent years in the clinical and molecular delineation of CdLS, necessitating a revision of the diagnostic criteria, more inclusive of the milder cases. In addition, a scoring system of severity has been found to correlate with specific brain changes. Thus, a clinical overview and recommendations for anticipatory guidance are timely in aiding caretakers and professionals to individualize care decisions and maximize developmental potential for individuals with CdLS. These guidelines are derived from consensus based on collective experience of over 500 patients with CdLS, observations of the natural history in children, adolescents, and adults, a review of the literature, and contacts with national support organizations in North America and Europe.

    Title Additional Clinical Manifestations in Children with Sensorineural Hearing Loss and Biallelic Gjb2 Mutations: Who Should Be Offered Gjb2 Testing?
    Date August 2007
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Sensorineural hearing loss (SNHL), the most common sensory impairment noted at birth, occurs in 3 out of every 1,000 births live births. At least half of congenital SNHL is genetic in origin, with nonsyndromic, or isolated hearing loss, accounting for approximately 70% of the total genetic causes. Syndromic hearing loss (hearing loss associated with other clinical findings) makes up the remaining 30%. Worldwide, mutations in the gap junction beta 2 (GJB2) gene, encoding the connexin 26 (Cx26) protein, are responsible for approximately 30% of all cases of childhood SNHL. GJB2 mutations have been primarily associated with nonsyndromic forms of bilateral SNHL although rare syndromic forms involving dermatologic manifestations have also been reported. In general, unless skin findings are present, children with bilateral SNHL and other structural or developmental abnormalities are not generally thought of as candidates for GJB2 testing. We evaluated 163 individuals with biallelic GJB2 mutations and SNHL for the presence of other clinical findings. Twenty-nine of the 163 (18%) were found to have structural and/or developmental abnormalities in addition to the SNHL and four subjects had diagnoses that were felt to account for their hearing loss prior to being screened for GJB2 mutations. Although the GJB2 mutations are likely not responsible for these additional clinical manifestations, this study underscores the importance of considering GJB2 mutational analysis in individuals with more than just isolated SNHL given the high prevalence of GJB2-related hearing loss.

    Title Mutations in Cohesin Complex Members Smc3 and Smc1a Cause a Mild Variant of Cornelia De Lange Syndrome with Predominant Mental Retardation.
    Date April 2007
    Journal American Journal of Human Genetics
    Excerpt

    Mutations in the cohesin regulators NIPBL and ESCO2 are causative of the Cornelia de Lange syndrome (CdLS) and Roberts or SC phocomelia syndrome, respectively. Recently, mutations in the cohesin complex structural component SMC1A have been identified in two probands with features of CdLS. Here, we report the identification of a mutation in the gene encoding the complementary subunit of the cohesin heterodimer, SMC3, and 14 additional SMC1A mutations. All mutations are predicted to retain an open reading frame, and no truncating mutations were identified. Structural analysis of the mutant SMC3 and SMC1A proteins indicate that all are likely to produce functional cohesin complexes, but we posit that they may alter their chromosome binding dynamics. Our data indicate that SMC3 and SMC1A mutations (1) contribute to approximately 5% of cases of CdLS, (2) result in a consistently mild phenotype with absence of major structural anomalies typically associated with CdLS, and (3) in some instances, result in a phenotype that approaches that of apparently nonsyndromic mental retardation.

    Title Notch2 Mutations Cause Alagille Syndrome, a Heterogeneous Disorder of the Notch Signaling Pathway.
    Date August 2006
    Journal American Journal of Human Genetics
    Excerpt

    Alagille syndrome (AGS) is caused by mutations in the gene for the Notch signaling pathway ligand Jagged1 (JAG1), which are found in 94% of patients. To identify the cause of disease in patients without JAG1 mutations, we screened 11 JAG1 mutation-negative probands with AGS for alterations in the gene for the Notch2 receptor (NOTCH2). We found NOTCH2 mutations segregating in two families and identified five affected individuals. Renal manifestations, a minor feature in AGS, were present in all the affected individuals. This demonstrates that AGS is a heterogeneous disorder and implicates NOTCH2 mutations in human disease.

    Title Jagged1 (jag1) Mutations in Alagille Syndrome: Increasing the Mutation Detection Rate.
    Date June 2006
    Journal Human Mutation
    Excerpt

    Alagille syndrome (AGS) is caused by heterozygous mutations in JAG1, and mutations have been previously reported in about 70% of patients who meet clinical diagnostic criteria. We studied a cohort of 247 clinically well-defined patients, and using an aggressive and sequential screening approach we identified JAG1 mutations in 94% of individuals. Mutations were found in 232 out of 247 patients studied and 83 of the mutations were novel. This increase in the mutation rate was accomplished by combining rigorous clinical phenotyping, with a combination of mutation detection techniques, including fluorescence in situ hybridization (FISH), genomic and cDNA sequencing, and quantitative PCR. This higher rate of mutation identification has implications for clinical practice, facilitating genetic counseling, prenatal diagnosis, and evaluation of living-related liver transplant donors. Our results suggest that more aggressive screening may similarly increase the rate of mutation detection in other dominant and recessive disorders.

    Title Ophthalmologic Findings in Cornelia De Lange Syndrome: a Genotype-phenotype Correlation Study.
    Date April 2006
    Journal Archives of Ophthalmology
    Excerpt

    OBJECTIVE: To evaluate individuals with Cornelia de Lange syndrome previously screened for mutations in the NIPBL gene for genotype-phenotype correlations with regard to severity of ophthalmologic findings. METHODS: Fifty-four patients with Cornelia de Lange syndrome (26 mutation positive and 28 mutation negative) with varying extent and severity of ophthalmologic findings participated in the study. We conducted a retrospective analysis of ophthalmologic data obtained through survey responses and medical records. The severity of nasolacrimal duct obstruction, myopia, ptosis, and strabismus was classified. The severity of eye findings was compared relative to the presence vs the absence of mutations in the coding region of NIPBL and relative to mutations predicted to result in a truncated protein (nonsense and frameshift mutations) vs missense mutations. Fisher exact test was used to determine the significance of these correlations. RESULTS: A trend toward increased ptosis severity was found among individuals with truncating (nonsense and frameshift) mutations compared with individuals with missense mutations (P = .07). CONCLUSION: NIPBL may be directly involved in ptosis pathogenesis. CLINICAL RELEVANCE: Elucidating the pathogenetic mechanisms of ophthalmologic morbidities in patients with de Lange syndrome may lead to more effective treatment.

    Title Intracranial Vascular Abnormalities in Patients with Alagille Syndrome.
    Date November 2005
    Journal Journal of Pediatric Gastroenterology and Nutrition
    Excerpt

    OBJECTIVES: To define the spectrum of intracranial events and cerebrovascular lesions in patients with Alagille syndrome using magnetic resonance imaging with angiography of the head and medical histories and to correlate the presence of lesions with the clinical outcome of bleeding or ischemic intracranial events. METHODS: 26 patients with Alagille syndrome underwent magnetic resonance imaging with angiography of the head; 22 had no symptoms and underwent study for screening purposes and 4 were symptomatic with neurologic changes. The results of studies and the history of ischemic intracranial events were reviewed. RESULTS: Cerebrovascular abnormalities were detected in 10 of 26 (38%) patients (9 by head magnetic resonance imaging with angiography and 1 by necropsy). The findings included stenoses of the internal carotid arteries unilaterally (n = 5) or bilaterally (n = 3), basilar artery aneurysm (n = 1) and middle cerebral artery aneurysm (n = 1). Among the 9 patients with cerebrovascular abnormalities detected by magnetic resonance imaging with angiography, 5 had no symptoms (23%, 5 of 22) and 4 were symptomatic. Thus, 100% of symptomatic patients had detected abnormalities and 23% of screened, asymptomatic patients had detected anomalies. Screening magnetic resonance imaging with angiography failed to detect vascular anomalies in 2 asymptomatic patients who had fatal ischemic intracranial events years later. There was evidence of progression of vascular abnormalities in 4 patients. Ischemic intracranial events occurred in 10 of 26 (38%) patients and were associated with cerebrovascular abnormalities in 6 of 10 patients. CONCLUSION: The cerebral vasculopathy of Alagille syndrome predominantly involves the internal carotid arteries. It is more prevalent than would be suggested by the number of symptomatic individuals, appears to be progressive and shares many similarities with moyamoya. Magnetic resonance imaging with angiography is useful to detect these lesions and may have a valuable role in screening for treatable lesions such as aneurysms.

    Title Chromosome Rearrangements in Cornelia De Lange Syndrome (cdls): Report of a Der(3)t(3;12)(p25.3;p13.3) in Two Half Sibs with Features of Cdls and Review of Reported Cdls Cases with Chromosome Rearrangements.
    Date October 2005
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited disorder characterized by multisystem involvement, cognitive delay, limb defects, and characteristic facial features. Recently, mutations in NIPBL have been found in approximately 50% of individuals with CdLS. Numerous chromosomal rearrangements have been reported in individuals with CdLS. These rearrangements may be causative of a CdLS phenotype, result in a phenocopy, or be unrelated to the observed phenotype. We describe two half siblings with a der(3)t(3;12)(p25.3;p13.3) chromosomal rearrangement, clinical features resembling CdLS, and phenotypic overlap with the del(3)(p25) phenotype. Region-specific BAC probes were used to fine-map the breakpoint region by fluorescence in situ hybridization (FISH). FISH analysis places the chromosome 3 breakpoint distal to RP11-115G3 on 3p25.3; the chromosome 12 breakpoint is distal to BAC RP11-88D16 on 12p13.3. A review of published cases of terminal 3p deletions and terminal 12p duplications indicates that the findings in these siblings are consistent with the del(3)(p25) phenotype. Given the phenotypic overlap with CdLS, we have reviewed the reported cases of chromosomal rearrangements involved in CdLS to better elucidate other potential loci that could harbor additional CdLS genes. Additionally, to identify chromosome rearrangements, genome-wide array comparative genomic hybridization (CGH) was performed on eight individuals with typical CdLS and without identifiable deletion or mutation of NIPBL. No pathologic rearrangements were identified.

    Title Precocious Sister Chromatid Separation (pscs) in Cornelia De Lange Syndrome.
    Date September 2005
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    The Cornelia de Lange syndrome (CdLS) (OMIM# 122470) is a dominantly inherited multisystem developmental disorder. The phenotype consists of characteristic facial features, hirsutism, abnormalities of the upper extremities ranging from subtle changes in the phalanges and metacarpal bones to oligodactyly and phocomelia, gastroesophageal dysfunction, growth retardation, and neurodevelopmental delay. Prevalence is estimated to be as high as 1 in 10,000. Recently, mutations in NIPBL were identified in sporadic and familial CdLS cases. To date, mutations in this gene have been identified in over 45% of individuals with CdLS. NIPBL is the human homolog of the Drosophila Nipped-B gene. Although its function in mammalian systems has not yet been elucidated, sequence homologs of Nipped-B in yeast (Scc2 and Mis4) are required for sister chromatid cohesion during mitosis, and a similar role was recently demonstrated for Nipped-B in Drosophila. In order to evaluate NIPBL role in sister chromatid cohesion in humans, metaphase spreads on 90 probands (40 NIPBL mutation positive and 50 NIPBL mutation negative) with CdLS were evaluated for evidence of precocious sister chromatid separation (PSCS). We screened 50 metaphases from each proband and found evidence of PSCS in 41% (compared to 9% in control samples). These studies indicate that NIPBL may play a role in sister chromatid cohesion in humans as has been reported for its homologs in Drosophila and yeast.

    Title Subtelomeric Deletions of Chromosome 6p: Molecular and Cytogenetic Characterization of Three New Cases with Phenotypic Overlap with Ritscher-schinzel (3c) Syndrome.
    Date May 2005
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    We have identified six children in three families with subtelomeric deletions of 6p25 and a recognizable phenotype consisting of ptosis, posterior embryotoxon, optic nerve abnormalities, mild glaucoma, Dandy-Walker malformation, hydrocephalus, atrial septal defect, patent ductus arteriosus, and mild mental retardation. There is considerable clinical overlap between these children and individuals with the Ritscher-Schinzel (or cranio-cerebello-cardiac (3C)) syndrome (OMIM #220210). Clinical features of 3C syndrome include craniofacial anomalies (macrocephaly, prominent forehead and occiput, foramina parietalia, hypertelorism, down-slanting palpebral fissures, ocular colobomas, depressed nasal bridge, narrow or cleft palate, and low-set ears), cerebellar malformations (variable manifestations of a Dandy-Walker malformation with moderate mental retardation), and cardiac defects (primarily septal defects). Since the original report, over 25 patients with 3C syndrome have been reported. Recessive inheritance has been postulated based on recurrence in siblings born to unaffected parents and parental consanguinity in two familial cases. Molecular and cytogenetic mapping of the 6p deletions in these three families with subtelomeric deletions of chromosome 6p have defined a 1.3 Mb minimally deleted critical region. To determine if 6p deletions are common in 3C syndrome, we analyzed seven unrelated individuals with 3C syndrome for deletions of this region. Three forkhead genes (FOXF1 and FOXQ1 from within the critical region, and FOXC1 proximal to this region) were evaluated as potential candidate disease genes for this disorder. No deletions or disease-causing mutations were identified.

    Title Subtelomeric Deletions of Chromosome 9q: a Novel Microdeletion Syndrome.
    Date February 2005
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Fluorescent in situ hybridization (FISH) screening of subtelomeric rearrangements has resulted in the identification of previously unrecognized chromosomal causes of mental retardation with and without dysmorphic features. This article reports the phenotypic and molecular breakpoint characterization in a cohort of 12 patients with subtelomeric deletions of chromosome 9q34. The phenotypic findings are consistent amongst these individuals and consist of mental retardation, distinct facial features and congenital heart defects (primarily conotruncal defects). Detailed breakpoint mapping by FISH, microsatellite and single nucleotide polymorphism (SNP) genotyping analysis has narrowed the commonly deleted region to an approximately 1.2 Mb interval containing 14 known transcripts. The majority of the proximal deletion breakpoints fall within a 400 kb interval between SNP markers C12020842 proximally and C80658 distally suggesting a common breakpoint in this interval.

    Title Nipbl Mutational Analysis in 120 Individuals with Cornelia De Lange Syndrome and Evaluation of Genotype-phenotype Correlations.
    Date December 2004
    Journal American Journal of Human Genetics
    Excerpt

    The Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphia, upper-extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities. Both missense and protein-truncating mutations in NIPBL, the human homolog of the Drosophila melanogaster Nipped-B gene, have recently been reported to cause CdLS. The function of NIPBL in mammals is unknown. The Drosophila Nipped-B protein facilitates long-range enhancer-promoter interactions and plays a role in Notch signaling and other developmental pathways, as well as being involved in mitotic sister-chromatid cohesion. We report the spectrum and distribution of NIPBL mutations in a large well-characterized cohort of individuals with CdLS. Mutations were found in 56 (47%) of 120 unrelated individuals with sporadic or familial CdLS. Statistically significant phenotypic differences between mutation-positive and mutation-negative individuals were identified. Analysis also suggested a trend toward a milder phenotype in individuals with missense mutations than in those with other types of mutations.

    Title A Giant Novel Gene Undergoing Extensive Alternative Splicing is Severed by a Cornelia De Lange-associated Translocation Breakpoint at 3q26.3.
    Date September 2004
    Journal Human Genetics
    Excerpt

    Cornelia de Lange syndrome (CdLS) is a rare developmental malformation syndrome characterised by mental handicap, growth retardation, distinctive facial features and limb reduction defects. The vast majority of CdLS cases are sporadic. We carried out a high density bacterial artificial chromosome (BAC) microarray comparative genome hybridisation screen but no evidence was found for a consistent pattern of microdeletion/microduplication. As an alternative, we focused on identifying chromosomal regions spanning associated translocation breakpoints. We prioritised the distal 3q region because of the occurrence, in a classical CdLS patient, of a de novo balanced translocation with a breakpoint at 3q26.3 and of reports of phenotypic overlap between cases of mild CdLS and individuals trisomic for the 3q26-q27 region. We show that the 3q26.3 breakpoint severs a previously uncharacterised giant gene, NAALADL2, containing at least 32 exons spanning 1.37 Mb. Northern blot analysis identified up to six different transcripts in the 1-10 kb range with strongest expression in kidney and placenta; embryonic expression was largely confined to duodenal and stomach endoderm, mesonephros, metanephros and pancreas. Transcript analysis identified extensive alternative splicing leading to multiple 5' and 3' untranslated regions and variable coding sequences. Multiple protein isoforms were defined by different N-terminal regions (with at least four alternative initiating methionine codons), and by differential protein truncation/use of alternative C-terminal sequences attributable to alternative splicing/polyadenylation. Outside the N-terminal regions, the predicted proteins showed significant homology to N-acetylated alpha-linked acidic dipeptidase and transferrin receptors. Mutation screening of NAALADL2 in a panel of CdLS patient DNA samples failed to identify patient-specific mutations. We discuss the possibility that the 3q26.3 translocation could nevertheless contribute to pathogenesis.

    Title Vascular Anomalies in Alagille Syndrome: a Significant Cause of Morbidity and Mortality.
    Date July 2004
    Journal Circulation
    Excerpt

    BACKGROUND: Alagille syndrome (AGS) is a dominantly inherited multisystem disorder involving the liver, heart, eyes, face, and skeleton, caused by mutations in Jagged1. Intracranial bleeding is a recognized complication and cause of mortality in AGS. There are multiple case reports of intracranial vessel abnormalities and other vascular anomalies in AGS. The objective of this study was to characterize the nature and spectrum of vascular anomalies in AGS. METHODS AND RESULTS: Retrospective chart review of 268 individuals with AGS was performed. Twenty-five patients (9%) had noncardiac vascular anomalies or events. Sixteen patients had documented structural vascular abnormalities. Two had basilar artery aneurysms, 7 had internal carotid artery anomalies, and another had a middle cerebral artery aneurysm. Moyamoya disease was described in 1 patient. Three of the 16 patients had aortic aneurysms, and 2 had aortic coarctations. One of the patients with a basilar artery aneurysm also had coarctation of the aorta. One of the individuals with an internal carotid artery anomaly also had renal artery stenosis. Nine more patients had intracranial events without documented vessel abnormalities. Vascular accidents accounted for 34% of the mortality in this cohort. CONCLUSIONS: The vascular anomalies described in our cohort of AGS individuals identify an underrecognized and potentially devastating complication of this disorder. It is a major cause of morbidity and mortality in this population, accounting for 34% of the mortality. We have also reviewed the body of evidence supporting a role for Jagged1 and the Notch signaling pathway in vascular development.

    Title Cornelia De Lange Syndrome is Caused by Mutations in Nipbl, the Human Homolog of Drosophila Melanogaster Nipped-b.
    Date June 2004
    Journal Nature Genetics
    Excerpt

    Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder characterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features. Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur. Prevalence is estimated to be as high as 1 in 10,000 (ref. 4). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CdLS with a de novo t(5;13)(p13.1;q12.1) translocation, allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CdLS. We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS. We characterized the genomic structure of NIPBL and found that it is widely expressed in fetal and adult tissues. The fly homolog of NIPBL, Nipped-B, facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster.

    Title Consequences of Jag1 Mutations.
    Date February 2004
    Journal Journal of Medical Genetics
    Excerpt

    BACKGROUND: Alagille syndrome (AGS) is a multi-system, autosomal dominant disorder with highly variable expressivity, caused by mutations within the Jagged1 (JAG1) gene. METHODS: We studied 53 mutation positive relatives of 34 AGS probands to ascertain the frequency of clinical findings in JAG1 mutation carriers. RESULTS: Eleven of 53 (21%) mutation positive relatives had clinical features that would have led to a diagnosis of AGS. Seventeen of the 53 (32%) relatives had mild features of AGS, revealed only after targeted evaluation following the diagnosis of a proband in their family. Twenty five of the 53 (47%) mutation positive relatives did not meet clinical criteria, and two of these individuals had no features consistent with AGS at all. The frequency of cardiac and liver disease was notably lower in the relatives than in the probands, characterising the milder end of the phenotypic spectrum. The characteristic facies of AGS was the feature with the highest penetrance, occurring almost universally in mutation positive probands and relatives. CONCLUSIONS: This study has implications for genetic counselling of families with AGS and JAG1 mutations.

    Title Homozygosity for the V37i Connexin 26 Mutation in Three Unrelated Children with Sensorineural Hearing Loss.
    Date July 2003
    Journal Clinical Genetics
    Excerpt

    Mutations in the Connexin 26 (Cx26) gene have been found to account for approximately 20% of all childhood deafness. This number approaches 50% in documented recessive cases of hearing loss. Two mutations, 35delG and 167delT, account for the majority of reported mutations in this gene, but to date, more than 60 mutations have been described. No other single gene has yet been identified that contributes this significantly to the aetiology of hearing loss. Several mutations in this gene have been found to predominate in specific ethnic populations (167delT in Ashkenazi Jews and 235delC in Japanese individuals). While the majority of mutations found in Cx26 result in frame shifts and premature terminations, a number of missense mutations have also been identified. The V37I missense mutation has been reported as both a polymorphism and as a potentially disease-causing missense mutation. The present authors have identified three unrelated individuals with sensorineural hearing loss who are homozygous for this mutation. One individual is of Philippine ancestry, another is from a Chinese and Cambodian background, while the third is of Chinese ancestry, raising the possibility that this mutation may be more frequent among populations in eastern Asia.

    Title Facial Features in Alagille Syndrome: Specific or Cholestasis Facies?
    Date March 2003
    Journal American Journal of Medical Genetics
    Excerpt

    Alagille syndrome is a complex multisystem disorder characterized by bile duct paucity, cholestasis, cardiac defects, vertebral anomalies, ophthalmologic changes, and facial dysmorphism. Although the facial features are highly conserved in affected individuals both within and between families, the possibility has been raised that cholestasis is the causative factor for the facies. In this study, the diagnostic specificity of the facies in Alagille syndrome has been evaluated by asking clinical dysmorphologists to examine a photographic panel of 18 pediatric and adult individuals with Alagille syndrome and other forms of congenital intrahepatic cholestasis. The examiners had no knowledge of the actual diagnoses. The group was able to distinguish correctly between Alagille and non-Alagille individuals with a frequency of 79%. Professional grade of the respondent did not affect the accuracy of correct identification. The adult facial features were the most difficult to evaluate successfully. The sensitivity of facies identification to diagnose Alagille syndrome was 76%, the specificity 82%, the positive predictive value 81%, and the negative predictive value 77%. These results suggest that the facies seen in Alagille syndrome is specific to this condition and its recognition is a valuable tool in diagnosis.

    Title Supernumerary Digital Flexion Creases: an Additional Clinical Manifestation of Alagille Syndrome.
    Date March 2003
    Journal American Journal of Medical Genetics
    Excerpt

    Alagille syndrome (AGS; OMIM 118450) is a complex dominantly inherited multisystem disorder involving the liver, heart, eyes, facies, skeleton, and other systems. Criteria for the clinical diagnosis have been established as the presence of bile duct paucity on liver biopsy in association with three of five major clinical findings (cholestasis, butterfly vertebrae, posterior embryotoxon, congenital heart disease, and facial features). Jagged1 has been identified as the AGS disease gene. Jagged1 is a large gene, with no mutational hot spots, making molecular testing difficult at this time. Other clinical features would prove helpful in establishing the diagnosis in the absence of molecular confirmation. Supernumerary digital flexion creases have been identified in 16/46 (35%) of AGS probands examined through the Alagille Syndrome Diagnostic Center at the Children's Hospital of Philadelphia. Although digital abnormalities have been noted in AGS in the past, including short distal phalanges and fifth finger clinodactyly, digital crease abnormalities have never before been reported. Supernumerary digital creases have been reported in less than 1% of the general population. The presence of extra and missing digital creases in individuals with normal joint anatomy, their occurrence in several syndromes, and mouse in situ expression studies indicate that genetic factors contribute to digital crease formation. However, these factors are poorly understood. Hypotheses regarding the origin of flexion creases are discussed. The identification of supernumerary digital creases in one-third of AGS probands provides another diagnostic aid and allows for speculation of the role of Jagged1 in the molecular development of digital crease patterns.

    Title Craniosynostosis in Alagille Syndrome.
    Date March 2003
    Journal American Journal of Medical Genetics
    Excerpt

    Alagille syndrome is a multisystem developmental disorder with primary involvement of the liver, heart, skeleton, eyes and facial structures, and demonstrates highly variable expressivity with respect to all of the involved systems. Alagille syndrome is caused by mutations in the Jagged1 gene. Jagged1 is a ligand in the Notch signaling pathway that has been shown to regulate early cell fate determination. Mutations in Jagged1 have been identified in approximately 80% of patients with Alagille syndrome. We have recently identified two patients with mutation proven Alagille syndrome who also had unilateral coronal craniosynostosis. Both individuals were screened for mutations in fibroblast growth factor receptor 1, 2, 3 and TWIST genes, all associated with various types of craniosynostosis and no mutations were identified. The finding of a conserved form of craniosynostosis in two unrelated patients with Alagille syndrome and mutations in Jagged1 may indicate that Jagged1 plays a role in cranial suture formation.

    Title Alagille Syndrome Inherited from a Phenotypically Normal Mother with a Mosaic 20p Microdeletion.
    Date March 2003
    Journal American Journal of Medical Genetics
    Excerpt

    We report an 18-month-old girl with Alagille syndrome, caused by a submicroscopic deletion of chromosome 20p, including the Jagged1 (JAG1) gene. FISH using a BAC probe containing JAG1 identified the deletion. Chromosomes were normal at the 550 band level. The deletion was inherited from her phenotypically normal mother who was found to have the deletion in 9/20 cells studied from peripheral blood. This is the first report of a JAG1 deletion inherited from an apparently unaffected mosaic parent.

    Title Monozygotic Twins with a Severe Form of Alagille Syndrome and Phenotypic Discordance.
    Date March 2003
    Journal American Journal of Medical Genetics
    Excerpt

    Alagille syndrome is an autosomal dominant disorder affecting multiple organ systems, predominantly the liver, heart, skeleton, eye, face, and kidney. The phenotype in Alagille syndrome is highly variable both within and between families. We report monozygotic twins with Alagille syndrome concordant for a mutation in Jagged1 but discordant for clinical phenotype. The twins' monozygosity was confirmed by molecular testing. A de novo splice site mutation was identified in exon 6 (1329 + 2T --> G) in both children. Both twins display a severe form of Alagille syndrome; however, one twin has a severe pulmonary atresia with mild liver involvement, while the other has tetralogy of Fallot and severe hepatic involvement, which has required liver transplantation. Potential mechanisms for phenotypic variability among monozygotic twins are discussed. This is the first reported case of discordance in phenotype in monozygotic twins with Alagille syndrome. This case implies that genotypic variations alone do not explain the clinical variability seen in Alagille syndrome and supports the contributory role of nongenetic factors in phenotype determination.

    Title Analysis of Cardiovascular Phenotype and Genotype-phenotype Correlation in Individuals with a Jag1 Mutation And/or Alagille Syndrome.
    Date November 2002
    Journal Circulation
    Excerpt

    BACKGROUND: Cardiovascular anomalies are among the most common features of Alagille syndrome (AGS). Mutations of JAG1 are found in most individuals with AGS. This study was undertaken to determine the spectrum of cardiovascular phenotypes associated with a JAG1 mutation and/or AGS, investigate potential genotype-phenotype correlations, and begin to correlate clinical outcome with genetic pathogenesis. METHODS AND RESULTS: We reviewed the records of 200 individuals with a JAG1 mutation or AGS. A total of 187 (94%) subjects had evidence of cardiovascular involvement. Cardiovascular anomalies were identified by imaging in 150 subjects (75%), and 37 (19%) had a peripheral pulmonary stenosis murmur with either a normal echocardiogram or no imaging study. Of the 150 subjects with anomalies confirmed by imaging, right-sided anomalies were present in 123 and left-sided anomalies in 22, with both in 12. Seventeen subjects had other anomalies. The most common abnormality was stenosis/hypoplasia of the branch pulmonary arteries (PAs), which was documented by imaging (n=111) or inferred from a peripheral pulmonary stenosis murmur (n=41) in 76% of subjects. Tetralogy of Fallot was present in 23 subjects and was accompanied by pulmonary atresia in 8. Branch PA phenotype differed between individuals with and without a JAG1 mutation. Among subjects with a JAG1 mutation, there was no correlation between the type or location of mutation and the frequency or type of cardiovascular anomaly. CONCLUSIONS: More than 90% of individuals with a JAG1 mutation or AGS have cardiovascular anomalies, with branch PA stenosis the most common abnormality. Cardiovascular phenotype does not correlate with the type or location of JAG1 mutation.

    Title Dominant Paternal Transmission of Cornelia De Lange Syndrome: a New Case and Review of 25 Previously Reported Familial Recurrences.
    Date January 2002
    Journal American Journal of Medical Genetics
    Excerpt

    The Cornelia de Lange syndrome (CdLS) is an autosomal dominant multisystem disorder characterized by somatic and cognitive retardation, characteristic facial features, limb abnormalities, hearing loss, and other organ system involvement. The vast majority of cases (99%) are sporadic, with rare familial occurrences having been reported. Most individuals with CdLS do not reproduce as a result of the severity of the disorder. Maternal transmission has been well documented, as have several cases of multiple-affected children being born to apparently unaffected parents. Paternal transmission has rarely been reported. A case is reported here of a father with classic features of CdLS with a similarly affected daughter. A review of the reported familial cases of CdLS is summarized.

    Title Mutation Analysis of Jagged1 (jag1) in Alagille Syndrome Patients.
    Date August 2001
    Journal Human Mutation
    Excerpt

    Alagille syndrome (AGS) is an autosomal dominant disorder caused by mutations in Jagged1 (JAG1), a ligand in the evolutionarily conserved Notch signaling pathway. Previous studies have demonstrated that a wide spectrum of JAG1 mutations result in AGS. These include total gene deletions, protein truncating, splicing and missense mutations which are distributed across the coding region of the gene. Here we present results of JAG1 mutation screening by SSCP and FISH in 105 patients with AGS. For these studies, new primers were designed for 12 exons. Mutations were identified in 63/105 patients (60%). The spectrum of the JAG1 mutations presented here is consistent with previously reported results. Eighty three percent (52/63) of the mutations were protein truncating, 11% (7/63) were missense, 2% (1/63) were splice site, and 5% (3/63) were total gene deletions demonstrable by FISH. Six of the missense mutations are novel. As has been reported previously, there is no apparent relationship between genotype and clinical phenotype.

    Title Duplication of Chromosome Region 4q28.3-qter in Monozygotic Twins with Discordant Phenotypes.
    Date October 2000
    Journal American Journal of Medical Genetics
    Excerpt

    We describe monozygotic twins with partially discordant phenotypes who were found to have a duplication of chromosome region 4q28.3-qter. The duplicated region of chromosome 4 resulted from an unbalanced segregation of a balanced maternal (4;22)(q28.3;p13) translocation. Duplication of the long arm of chromosome 4 has been described in >60 patients; however, it usually results from the unbalanced segregation of a parental balanced translocation and has an associated monosomy. Twenty cases of dup 4q without an associated monosomy have been reported, and this is the only case of dup 4q28. 3-qter. All cases of dup 4q are reviewed, and phenotypic aspects are analyzed. Issues of monozygotic twinning and other birth defects also are addressed.

    Title Clinical and Molecular Genetics of Alagille Syndrome.
    Date December 1999
    Journal Current Opinion in Pediatrics
    Excerpt

    Alagille syndrome (AGS) is a dominantly inherited disorder characterized by bile duct paucity and resultant liver disease in combination with cardiac, skeletal, ocular, and facial abnormalities. Jagged1 (JAG1) has been identified as the AGS disease gene. It encodes a ligand in the Notch signaling pathway that is involved in cell fate determination. AGS is the first developmental disorder to be associated with this pathway. It shows highly variable expressivity, and diagnosis in mildly affected persons can be difficult without molecular analysis. Currently, JAG1 mutations are detected in about 70% of patients with AGS and include total gene deletions as well as protein truncating, splicing, and missense mutations. Mutations are located across the gene within the evolutionarily conserved motifs of the protein. There is no phenotypic difference between patients with deletion of the entire JAG1 gene and those with intragenic mutations. This suggests that haploinsufficiency for JAG1 is a mechanism causing AGS.

    Title Jagged1 Mutations in Patients Ascertained with Isolated Congenital Heart Defects.
    Date May 1999
    Journal American Journal of Medical Genetics
    Excerpt

    Mutations in Jagged1 cause Alagille syndrome (AGS), a pleiotropic disorder with involvement of the liver, heart, skeleton, eyes, and facial structures. Cardiac defects are seen in more than 95% of AGS patients. Most commonly these are right-sided defects ranging from mild peripheral pulmonic stenosis to severe forms of tetralogy of Fallot. AGS demonstrates highly variable expressivity with respect to all of the involved systems. This leads us to hypothesize that defects in Jagged1 can be found in patients with presumably isolated heart defects, such as tetralogy of Fallot or pulmonic stenosis. Two patients with heart defects of the type seen in AGS and their relatives were investigated for alterations in the Jagged1 gene. Jagged1 was screened by a combination of cytogenetic and molecular techniques. Patient 1 was studied because of a four-generation history of pulmonic stenosis. Molecular analysis showed a point mutation in Jagged1 in the patient and her mother. Patient 2 was investigated owing to the finding of tetralogy of Fallot and a "butterfly" vertebra on chest radiograph first noted at age 5 years. She was found to have a deletion of chromosome region 20p12 that encompassed the entire Jagged1 gene. The identification of these two patients suggests that other patients with right-sided heart defects may have subtle findings of AGS and Jagged1 mutations.

    Title Features of Alagille Syndrome in 92 Patients: Frequency and Relation to Prognosis.
    Date March 1999
    Journal Hepatology (baltimore, Md.)
    Excerpt

    We have studied 92 patients with Alagille syndrome (AGS) to determine the frequency of clinical manifestations and to correlate the clinical findings with outcome. Liver biopsy specimens showed paucity of the interlobular ducts in 85% of patients. Cholestasis was seen in 96%, cardiac murmur in 97%, butterfly vertebrae in 51%, posterior embryotoxon in 78%, and characteristic facies in 96% of patients. Renal disease was present in 40% and intracranial bleeding or stroke occurred in 14% of patients. The presence of intracardiac congenital heart disease was the only clinical feature statistically associated with increased mortality (P <.001). Initial measures of hepatic function in infancy including absence of scintiscan excretion were not predictive of risk for transplantation or increased mortality. The hepatic histology of these AGS patients showed a significant increase in the prevalence of bile duct paucity (P =.002) and fibrosis (P <.001) with increasing age. Liver transplantation for hepatic decompensation was necessary in 21% (19 of 92) of patients with 79% survival 1-year posttransplantation. Current mortality is 17% (16 of 92). The factors that contributed significantly to mortality were complex congenital heart disease (15%), intracranial bleeding (25%), and hepatic disease or hepatic transplantation (25%). The 20-year predicted life expectancy is 75% for all patients, 80% for those not requiring liver transplantation, and 60% for those who required liver transplantation.

    Title Spectrum and Frequency of Jagged1 (jag1) Mutations in Alagille Syndrome Patients and Their Families.
    Date June 1998
    Journal American Journal of Human Genetics
    Excerpt

    Alagille syndrome (AGS) is a dominantly inherited disorder characterized by liver disease in combination with heart, skeletal, ocular, facial, renal, and pancreatic abnormalities. We have recently demonstrated that Jagged1 (JAG1) is the AGS gene. JAG1 encodes a ligand in the Notch intercellular signaling pathway. AGS is the first developmental disorder to be associated with this pathway and the first human disorder caused by a Notch ligand. We have screened 54 AGS probands and family members to determine the frequency of mutations in JAG1. Three patients (6%) had deletions of the entire gene. Of the remaining 51 patients, 35 (69%) had mutations within JAG1, identified by SSCP analysis. Of the 35 identified intragenic mutations, all were unique, with the exceptions of a 5-bp deletion in exon 16, seen in two unrelated patients, and a C insertion at base 1618 in exon 9, also seen in two unrelated patients. The 35 intragenic mutations included 9 nonsense mutations (26%); 2 missense mutations (6%); 11 small deletions (31%), 8 small insertions (23%), and 1 complex rearrangement (3%), all leading to frameshifts; and 4 splice-site mutations (11%). The mutations are spread across the coding sequence of the gene within the evolutionarily conserved motifs of the JAG1 protein. There is no phenotypic difference between patients with deletions of the entire JAG1 gene and those with intragenic mutations, which suggests that one mechanism involved in AGS is haploinsufficiency. The two missense mutations occur at the same amino acid residue. The mechanism by which these missense mutations lead to the disease is not yet understood; however, they suggest that mechanisms other than haploinsufficiency may result in the AGS phenotype.

    Title Killer/dr5 is a Dna Damage-inducible P53-regulated Death Receptor Gene.
    Date November 1997
    Journal Nature Genetics
    Title Mutations in the Human Jagged1 Gene Are Responsible for Alagille Syndrome.
    Date July 1997
    Journal Nature Genetics
    Excerpt

    Alagille syndrome (AGS) is an autosomal-dominant disorder characterized by intrahepatic cholestasis and abnormalities of heart, eye and vertebrae, as well as a characteristic facial appearance. Identification of rare AGS patients with cytogenetic deletions has allowed mapping of the gene of 20p12. We have generated a cloned contig of the critical region and used fluorescent in situ hybridization on cells from patients with submicroscopic deletions to narrow the candidate region to only 250 kb. Within this region we identified JAG1, the human homologue of rat Jagged1, which encodes a ligand for the Notch receptor. Cell-cell Jagged/Notch interactions are known to be critical for determination of cell fates in early development, making this an attractive candidate gene for a developmental disorder in humans. Determining the complete exon-intron structure of JAG1 allowed detailed mutational analysis of DNA samples from non-deletion AGS patients, revealing three frame-shift mutations, two splice donor mutations and one mutation abolishing RNA expression from the altered allele. We conclude that AGS is caused by haploinsufficiency of JAG1.

    Title Alagille Syndrome is Caused by Mutations in Human Jagged1, Which Encodes a Ligand for Notch1.
    Date July 1997
    Journal Nature Genetics
    Excerpt

    Alagille syndrome is an autosomal dominant disorder characterized by abnormal development of liver, heart, skeleton, eye, face and, less frequently, kidney. Analyses of many patients with cytogenetic deletions or rearrangements have mapped the gene to chromosome 20p12, although deletions are found in a relatively small proportion of patients (< 7%). We have mapped the human Jagged1 gene (JAG1), encoding a ligand for the developmentally important Notch transmembrane receptor, to the Alagille syndrome critical region within 20p12. The Notch intercellular signalling pathway has been shown to mediate cell fate decisions during development in invertebrates and vertebrates. We demonstrate four distinct coding mutations in JAG1 from four Alagille syndrome families, providing evidence that it is the causal gene for Alagille syndrome. All four mutations lie within conserved regions of the gene and cause translational frameshifts, resulting in gross alterations of the protein product Patients with cytogenetically detectable deletions including JAG1 have Alagille syndrome, supporting the hypothesis that haploinsufficiency for this gene is one of the mechanisms causing the Alagille syndrome phenotype.

    Title Deletions of 20p12 in Alagille Syndrome: Frequency and Molecular Characterization.
    Date June 1997
    Journal American Journal of Medical Genetics
    Excerpt

    Alagille syndrome is an autosomal dominant disorder comprising cholestasis (associated with intrahepatic bile duct paucity), characteristic facial appearance, and cardiac, ocular and skeletal defects. Multiple patients have been reported with deletions or translocation involving 20p11.23-p12, providing evidence for the localization of the disease gene to this region. Fifty-six Alagille syndrome patients have been studied by cytogenetic and/or molecular analysis to determine the frequency of detectable abnormalities of 20p12. Two of fifty-six patients studied by cytogenetic analysis had abnormalities: an interstitial deletion in one patient and a translocation in another. Of forty-five patients studied by molecular analysis, three were found to have deletions of 20p, including the two patients identified with cytogenetic abnormalities. Molecular and molecular cytogenetic (FISH) analysis of the translocation (46,XX,t(2;20)(q21.3p12)) demonstrated a deletion at the translocation breakpoint. The deletions identified in the three patients are overlapping, contributing to the delineation of an Alagille syndrome critical region within 20p12. This region lies between markers D20S41 and D20S162. The frequency of detectable cytogenetic abnormalities of 20p12 in this group of Alagille patients is 2/56 (3.6%), and the frequency of molecular deletions is 3/45 (6.7%). This is considerably lower than the frequency of deletions observed in contiguous gene deletion syndromes suggesting that Alagille syndrome may be caused by the alteration of a single gene.

    Title Alagille Syndrome.
    Date May 1997
    Journal Journal of Medical Genetics
    Excerpt

    Alagille syndrome (OMIM 118450) is an autosomal dominant disorder associated with abnormalities of the liver, heart, eye, skeleton, and a characteristic facial appearance. Also referred to as the Alagille-Watson syndrome, syndromic bile duct paucity, and arteriohepatic dysplasia, it is a significant cause of neonatal jaundice and cholestasis in older children. In the fully expressed syndrome, affected subjects have intrahepatic bile duct paucity and cholestasis, in conjunction with cardiac malformations (most frequently peripheral pulmonary stenosis), ophthalmological abnormalities (typically of the anterior chamber with posterior embryotoxon being the most common), skeletal anomalies (most commonly butterfly vertebrae), and characteristic facial appearance. Inheritance is autosomal dominant, but expressivity is highly variable. Sibs and parents of probands are often found to have mild expression of the presumptive disease gene, with abnormalities of only one or two systems. The frequency of new mutations appears relatively high, estimated at between 15 and 50%. The disease gene has been mapped to chromosome 20 band p12 based on multiple patients described with cytogenetic or molecular rearrangements of this region. However, the frequency of detectable deletions of 20p12 is low (less than 7%). Progress has been made in the molecular definition of an Alagille syndrome critical region within the short arm of chromosome 20. We will review the clinical, genetic, cytogenetic, and molecular findings in this syndrome.

    Title Outcomes of Clinical Examination and Genetic Testing of 500 Individuals with Hearing Loss Evaluated Through a Genetics of Hearing Loss Clinic.
    Date
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Hearing loss (HL) occurs in approximately 2 out of every 1,000 births and is genetic in origin in approximately 50% of cases. This high incidence coupled with the increasing number of genes implicated in HL and the trend toward universal newborn screening led to the establishment of the Genetics of Hearing Loss Clinic at The Children's Hospital of Philadelphia to manage the diagnosis, genetic screening, and counseling of families with an affected child. To date 500 individuals have been evaluated from 1999 to 2004. To determine the cause of their HL and screen for syndromic forms of HL, individuals were offered a panel of tests. Depending on the type and severity of the HL, recommendations included GJB2 mutation analysis, renal and thyroid function studies, a CT scan of the temporal bones, an ophthalmology evaluation, an EKG, and, at times, additional genetic tests. Of the 500 patients evaluated 70 (14%) had a syndromic etiology for their HL. Twenty-eight different syndromic etiologies were identified. Enlarged vestibular aqueducts (EVAs) and/or Mondini malformations were seen in 18% of individuals with HL who had a CT or MRI of the temporal bones. Genetic testing of the GJB2 gene was completed for 310 of the 377 patients with bilateral sensorineural HL (82.2%). Nineteen different variants were identified in the GJB2 gene. Through GJB2 mutational analysis, clinical examination, and laboratory testing, a definitive etiologic diagnosis was established in 110/500 (22%) of patients.

    Title Cornelia De Lange Syndrome: Clinical Review, Diagnostic and Scoring Systems, and Anticipatory Guidance Am J Med Genet Part A 143a:1287-1296.
    Date
    Journal American Journal of Medical Genetics. Part A
    Title Evaluating the Quality of Care Provided by Graduates of International Medical Schools.
    Date
    Journal Health Affairs (project Hope)
    Excerpt

    One-quarter of practicing physicians in the United States are graduates of international medical schools. The quality of care provided by doctors educated abroad has been the subject of ongoing concern. Our analysis of 244,153 hospitalizations in Pennsylvania found that patients of doctors who graduated from international medical schools and were not U.S. citizens at the time they entered medical school had significantly lower mortality rates than patients cared for by doctors who graduated from U.S. medical schools or who were U.S. citizens and received their degrees abroad. The patient population consisted of those with congestive heart failure or acute myocardial infarction. We found no significant mortality difference when comparing all international medical graduates with all U.S. medical school graduates.

    Title The Incidence of Thrombocytopenia in Children with Cornelia De Lange Syndrome.
    Date
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Thrombocytopenia was first reported in Cornelia de Lange syndrome (CdLS) by Froster in 1993. Despite early reports, thrombocytopenia has been rarely reported in this disorder. We performed a retrospective analysis of a large cohort of patients with CdLS. We calculated prevalence of thrombocytopenia in three subsets of this cohort: the entire cohort (n = 1,740), a subset of subjects with substantial clinical records (n = 695) and a subset of subjects with clinical information regarding platelet counts (n = 85). This analysis revealed that 15 have had thrombocytopenia (18% of those with available blood counts); seven had immune thrombocytopenia (ITP). The reported prevalence of pediatric ITP is between 5 and 13 per 100,000 persons. The prevalence of ITP in this cohort is between 7/1,740 and 7/85, giving a relative risk of ITP of between 30 (CI 12-77) and 633 (CI 259-1,549). Contrary to the reported cases in the literature, none of our patients have had progression of the thrombocytopenia nor have they developed other cytopenias. All 15 patients with thromobocytopenia had CdLS based on clinical criteria. Of the 10 patients tested for mutations in NIBPL, 8 had mutations identified. These data support an increased incidence of thrombocytopenia and ITP in CdLS. Subsequently, patients are at risk for spontaneous hemorrhage, and likely increased risk secondary to the high frequency of self-injurious behavior. Although further studies are needed to better define the scope of the problem and to define the mechanisms of thrombocytopenia in CdLS, we would recommend screening for thrombocytopenia upon diagnosis and at 5-year intervals thereafter. © 2010 Wiley-Liss, Inc.

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