Peter N Ray

Publications (29)95.99 Total impact

• Article: Mosaicism for genome-wide paternal uniparental disomy with features of multiple imprinting disorders: Diagnostic and management issues.

  Michal Inbar-Feigenberg, Sanaa Choufani, Cheryl Cytrynbaum, Yi-An Chen, Leslie Steele, Cheryl Shuman, Peter N Ray, Rosanna Weksberg
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  ABSTRACT: Mosaicism for genome-wide paternal uniparental disomy (UPD) has been reported in only seven live born individuals to date. Clinical presentation includes manifestations of multiple paternal UPD syndromes with high variability, likely due to the variable levels of mosaicism in different somatic tissues. We report an eighth case in a female patient with mosaicism for genome-wide paternal UPD which highlights the complex clinical presentation. Our patient had features of Beckwith-Wiedemann syndrome (BWS), Angelman syndrome, and congenital hyperinsulinism. The clinical findings included prematurity, organomegaly, hemihyperplasia, developmental delay, benign tumors, and cystic lesions. The diagnosis in our patient was established utilizing microarray-based genome-wide DNA methylation analysis performed on leukocyte DNA. Targeted multiplex ligation-dependent probe amplification (MLPA) analysis of chromosome regions 11p15 and 15q13 confirmed mosaicism for paternal UPD at these genomic regions. This case represents the first report of microarray-based genome-wide DNA methylation analysis in the diagnosis of genome-wide paternal UPD. The application of microarray-based genome-wide DNA methylation analysis on selected individuals with complex clinical presentations could be a valuable diagnostic tool to improve the detection rate of mosaic genome-wide paternal UPD. This approach, which screens many loci simultaneously, is more cost-effective and less labor-intensive than performing multiple targeted DNA methylation-based assays. Identification of individuals with mosaicism for genome-wide paternal UPD is an important goal as it confers a low recurrence risk for the family and identifies individuals who require surveillance due to increased tumor risk. © 2012 Wiley Periodicals, Inc.
  American Journal of Medical Genetics Part A 12/2012; · 2.39 Impact Factor
• Article: Brain abnormalities in patients with Beckwith-Wiedemann syndrome.

  Kate Gardiner, David Chitayat, Sanaa Choufani, Cheryl Shuman, Susan Blaser, Deborah Terespolsky, Sandra Farrell, Rosemary Reiss, Shoshana Wodak, Shuye Pu, Peter N Ray, Berivan Baskin, Rosanna Weksberg
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  ABSTRACT: Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with variability in clinical manifestations and molecular causes. In most cases, patients with BWS have normal development. Cases with developmental delay are usually attributed to neonatal hypoglycemia or chromosome abnormalities involving copy number variation for genes beyond the critical BWS region at 11p15.5. Brain abnormalities have not previously been recognized within the BWS phenotypic spectrum. We report on seven cases of BWS associated with posterior fossa abnormalities. Of these, two cases presented with Blake's pouch cyst, two with Dandy-Walker variant (DWV; hypoplasia of the inferior part of the vermis), one with Dandy-Walker malformation (DWM) and one with a complex of DWM, dysgenesis of the corpus callosum and brain stem abnormality. In all these cases, molecular findings involved the centromeric imprinted domain on chromosome locus 11p15.5, which includes imprinting center 2 (IC2) and the imprinted growth suppressor gene, CDKN1C. Three cases had loss of methylation at IC2, two had CDKN1C mutations, and one had loss of methylation at IC2 and a microdeletion. In one case no mutation/methylation abnormality was detected. These findings together with previously reported correlations suggest that genes in imprinted domain 2 at 11p15.5 are involved in normal midline development of several organs including the brain. Our data suggest that brain malformations may present as a finding within the BWS phenotype when the molecular etiology involves imprinted domain 2. Brain imaging may be useful in identifying such malformations in individuals with BWS and neurodevelopmental issues.
  American Journal of Medical Genetics Part A 05/2012; 158A(6):1388-94. · 2.39 Impact Factor
• Article: Milder phenotype of congenital muscular dystrophy in a novel POMT1 mutation.

  Samiah A Al-Zaidy, Berivan Baskin, Cynthia Hawkins, Grace Yoon, Peter N Ray, Jiri Vajsar
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  ABSTRACT: Congenital muscular dystrophies (CMD) with hypoglycosylated α-dystroglycan due to POMT1 mutations are associated with clinical phenotypes that vary in severity. We describe a patient with congenital hypotonia, generalized weakness, elevated creatine kinase (CK), and normal brain imaging. Histochemical analysis of the index case's muscle showed deficiency of glycosylated α-dystroglycan and secondary merosin deficiency. Genetic testing revealed a novel mutation in exon 20 of the POMT1 gene. Our patient's milder form of CMD adds to the emerging evidence of an expanding phenotype caused by POMT1 mutations. The histopathological findings of the muscle biopsy in this case support the need for careful clinical, genetic, and histochemical diagnostic interpretation.
  Muscle & Nerve 05/2012; 45(5):752-5. · 2.37 Impact Factor
• Article: Duchenne muscular dystrophy caused by a complex rearrangement between intron 43 of the DMD gene and chromosome 4.

  Berivan Baskin, William T Gibson, Peter N Ray
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  ABSTRACT: Deletions/duplications of exons in the DMD gene cause about 70% of all cases of Duchenne muscular dystrophy (DMD). Most remaining mutations are point mutations or small insertion-deletions located mainly in the coding but also in deep intronic regions of the DMD gene. We describe a novel complex rearrangement in a patient affected with DMD that was undetectable using standard molecular diagnostic methods. Analysis of the proband's mRNA from a muscle biopsy revealed the insertion of an 80 bp cryptic exon from chromosome 4 between exons 43 and 44 of the dystrophin gene. Array comparative genomic hybridization and breakpoint junction sequence analysis indicated this cryptic exon originated from a complex genomic 90 kb insertion of non-coding chromosome 4 into intron 43 of the dystrophin gene. This rearrangement was also detectable in the patient's mother. The genomic characterization of this novel complex mutation was essential for accurate carrier and genetic counseling of this family and emphasizes the need for comprehensive molecular diagnosis of patients with clinical signs of DMD and clear pathological changes.
  Neuromuscular Disorders 12/2010; 21(3):178-82. · 2.80 Impact Factor
• Article: A common molecular mechanism underlies two phenotypically distinct 17p13.1 microdeletion syndromes.

  Adam Shlien, Berivan Baskin, Maria Isabel W Achatz, Dimitrios J Stavropoulos, Kim E Nichols, Louanne Hudgins, Chantal F Morel, Margaret P Adam, Nataliya Zhukova, Lianne Rotin, Ana Novokmet, Harriet Druker, Mary Shago, Peter N Ray, Pierre Hainaut, David Malkin
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  ABSTRACT: DNA copy-number variations (CNVs) underlie many neuropsychiatric conditions, but they have been less studied in cancer. We report the association of a 17p13.1 CNV, childhood-onset developmental delay (DD), and cancer. Through a screen of over 4000 patients with diverse diagnoses, we identified eight probands harboring microdeletions at TP53 (17p13.1). We used a purpose-built high-resolution array with 93.75% breakpoint accuracy to fine map these microdeletions. Four patients were found to have a common phenotype including DD, hypotonia, and hand and foot abnormalities, constituting a unique syndrome. Notably, these patients were not affected with cancer. Moreover, none of the TP53-deletion patients affected with cancer (n = 4) had neurocognitive impairments. DD patients have larger deletions, which encompass but do not disrupt TP53, whereas cancer-affected patients harbor CNVs with at least one breakpoint within TP53. Most 17p13.1 deletions arise by Alu-mediated nonallelic homologous recombination. Furthermore, we identify a critical genomic region associated with DD and containing six underexpressed genes. We conclude that, although they overlap, 17p13.1 CNVs are associated with distinct phenotypes depending on the position of the breakpoint with respect to TP53. Further, detailed characterization of breakpoints revealed a common formation signature. Future studies should consider whether other loci in the genome also give rise to phenotypically distinct disorders by means of a common mechanism, resulting in a similar formation signature.
  The American Journal of Human Genetics 11/2010; 87(5):631-42. · 10.60 Impact Factor
• Article: Paternal isodisomy of chromosome 2 as a cause of long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency.

  Berivan Baskin, Michael Geraghty, Peter N Ray
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  ABSTRACT: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is an autosomal recessive disorder affecting mitochondrial fatty acid oxidation due to mutations in the HADHA gene. We report on a 22-month-old child who was identified on expanded newborn screening with an abnormal acylcarnitine pattern and increased C14OH. Molecular analysis showed that the child was homozygous for the common mutation, c.1526G > C (p.Glu510Gln) in the HADHA gene. Carrier testing on the parental samples revealed that the father was heterozygous for the mutation whereas the mother did not carry the mutation. Short tandem repeat testing with markers covering both short and long arms of chromosome 2 showed that the child has paternal uniparental isodisomy. We highlight the importance of parental testing in cases of homozygosity in autosomal recessive disorders and its impact on genetic counseling of the family.
  American Journal of Medical Genetics Part A 07/2010; 152A(7):1808-11. · 2.39 Impact Factor
• Article: Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations.

  Uri Tabori, Berivan Baskin, Mary Shago, Noa Alon, Michael D Taylor, Peter N Ray, Eric Bouffet, David Malkin, Cynthia Hawkins
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  ABSTRACT: Medulloblastoma is the prototype of treatment success in modern pediatric neuro-oncology. Unfortunately, 20% to 30% of tumors recur despite maximal resection and multimodal therapy. Multiple biologic prognostic markers have been investigated to predict recurrences, but controversy remains regarding their clinical utility. Because p53 immunopositivity is an adverse prognostic marker in pediatric medulloblastoma and TP53 mutations are associated with chemotherapy and radiation therapy resistance, we aimed to determine the extent and role of TP53 mutations in pediatric medulloblastoma treatment failure. One hundred eight of 111 consecutive patients diagnosed with medulloblastoma in our institution from 1995 to 2007 were included. Median follow-up time was 5.3 years in survivors. All samples were immunostained for p53 and erbB-2. Histologic grade and immunostaining were scored by two blinded reviewers. For 49 patients, frozen material was available for TP53 sequencing. The main outcome measures were overall and progression-free survival. Sixteen percent of sequenced medulloblastomas harbored a TP53 mutation. As a screening test, p53 immunohistochemistry was 100% sensitive and 83% specific for a TP53 mutation. Strikingly, all mutated tumors recurred early, and 5-year survival for average-risk patients was 0% for TP53-mutated medulloblastoma compared with 74% +/- 8% for wild-type medulloblastoma (P < .0001). Furthermore, 75% of recurrences in average-risk patients were associated with TP53 mutations. On multivariate analysis, TP53 mutation status was the strongest adverse prognostic factor (hazard ratio = 10.4, P = .003). Lack of long-term survival in TP53-mutated medulloblastomas highlights the role of TP53 mutations in medulloblastoma resistance to conventional therapies and the need for alternative treatments, and prospective validation of these findings is needed.
  Journal of Clinical Oncology 02/2010; 28(8):1345-50. · 18.37 Impact Factor
• Article: Recurrent focal copy-number changes and loss of heterozygosity implicate two noncoding RNAs and one tumor suppressor gene at chromosome 3q13.31 in osteosarcoma.

  Ivan Pasic, Adam Shlien, Adam D Durbin, Dimitrios J Stavropoulos, Berivan Baskin, Peter N Ray, Ana Novokmet, David Malkin
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  ABSTRACT: Osteosarcomas are copy number alteration (CNA)-rich malignant bone tumors. Using microarrays, fluorescence in situ hybridization, and quantitative PCR, we characterize a focal region of chr3q13.31 (osteo3q13.31) harboring CNAs in 80% of osteosarcomas. As such, osteo3q13.31 is the most altered region in osteosarcoma and contests the view that CNAs in osteosarcoma are nonrecurrent. Most (67%) osteo3q13.31 CNAs are deletions, with 75% of these monoallelic and frequently accompanied by loss of heterozygosity (LOH) in flanking DNA. Notably, these CNAs often involve the noncoding RNAs LOC285194 and BC040587 and, in some cases, a tumor suppressor gene that encodes the limbic system-associated membrane protein (LSAMP). Ubiquitous changes occur in these genes in osteosarcoma, usually involving loss of expression. Underscoring their functional significance, expression of these genes is correlated with the presence of osteo3q13.31 CNAs. Focal osteo3q13.31 CNAs and LOH are also common in cell lines from other cancers, identifying osteo3q13.31 as a generalized candidate region for tumor suppressor genes. Osteo3q13.31 genes may function as a unit, given significant correlation in their expression despite the great genetic distances between them. In support of this notion, depleting either LSAMP or LOC285194 promoted proliferation of normal osteoblasts by regulation of apoptotic and cell-cycle transcripts and also VEGF receptor 1. Moreover, genetic deletions of LOC285194 or BC040587 were also associated with poor survival of osteosarcoma patients. Our findings identify osteo3q13.31 as a novel region of cooperatively acting tumor suppressor genes.
  Cancer Research 01/2010; 70(1):160-71. · 7.86 Impact Factor
• Article: Becker muscular dystrophy caused by an intronic mutation reducing the efficiency of the splice donor site of intron 26 of the dystrophin gene.

  Berivan Baskin, Brenda Banwell, Reem Al Khater, Cynthia Hawkins, Peter N Ray
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  ABSTRACT: We describe an 11-year-old boy with dystrophinopathy who presented with a history of progressive proximal muscle weakness and elevated serum creatine kinase levels at age 6. Sequence analysis of the dystrophin (DMD) gene did not identify a mutation in the coding regions but revealed a nucleotide substitution in intron 26 (c.3603+3A>T). Since computer algorithms did not conclusively indicate that this sequence variant inactivated the splice site, we analyzed the DMD mRNA from a muscle biopsy of the patient to determine its functional significance. PCR and sequence analysis of the cDNA demonstrated that the mutation reduced the efficiency of the donor splice site and caused activation of a cryptic donor site 113 bp downstream. Activation of the cryptic donor site led to inclusion of 116 bp of intronic sequence containing a stop codon producing a truncated dystrophin protein. Residual wild-type splicing was also detected, which would explain the milder Becker rather than Duchenne phenotype in this patient. We highlight the importance of mRNA analysis for determination of pathogenicity in patients with ambiguous sequence variants in the DMD gene.
  Neuromuscular Disorders 03/2009; 19(3):189-92. · 2.80 Impact Factor
• Article: Walker-Warburg Syndrome with POMT1 mutations can be associated with cleft lip and cleft palate.

  Jiri Vajsar, Berivan Baskin, Kathryn Swoboda, Doug W Biggar, Harry Schachter, Peter N Ray
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  ABSTRACT: Walker-Warburg Syndrome (WWS) is an alpha-dystroglycan deficient congenital muscular dystrophy that is associated with brain and eye abnormalities. Patients present with hypotonia, weakness, developmental delay, mental retardation and occasional seizures. Other abnormalities were also described including cleft lip and palate. Mutations in POMT1, POMT2, fukutin, FKRP and LARGE genes are found in 20-30% of children with WWS. We report a novel mutation in POMT1 gene and provide further evidence that WWS with cleft lip and palate is associated with POMT1 mutations. We recommend POMT1 analysis in WWS cases associated with cleft lip and palate when considering which gene to sequence first.
  Neuromuscular Disorders 08/2008; 18(8):675-7. · 2.80 Impact Factor
• Source

  Available from: Eric Meslin

  Article: Research ethics recommendations for whole-genome research: consensus statement.

  Timothy Caulfield, Amy L McGuire, Mildred Cho, Janet A Buchanan, Michael M Burgess, Ursula Danilczyk, Christina M Diaz, Kelly Fryer-Edwards, Shane K Green, Marc A Hodosh, [......], Bartha Maria Knoppers, Trudo Lemmens, Eric M Meslin, Juli Murphy, Robert L Nussbaum, Margaret Otlowski, Daryl Pullman, Peter N Ray, Jeremy Sugarman, Michael Timmons
  PLoS Biology 04/2008; 6(3):e73. · 11.45 Impact Factor
• Article: Molecular diagnosis of 22q11.2 deletion and duplication by multiplex ligation dependent probe amplification.

  Andrea C Stachon, Berivan Baskin, Adam C Smith, Andrea Shugar, Cheryl Cytrynbaum, Leona Fishman, Roberto Mendoza-Londono, Regan Klatt, Ahmed Teebi, Peter N Ray, Rosanna Weksberg
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  ABSTRACT: 22q11 Deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans, occurring with an incidence of 1 in 4,000. In most cases the submicroscopic deletion spans 3 Mb, but there are a number of other overlapping and non-overlapping deletions that generate a similar phenotype. The majority of the 22q11.2 microdeletions can be ascertained using a standard fluorescence in situ hybridization (FISH) assay probing for TUPLE1 or N25 on 22q11.2. However, this test fails to detect deletions that are either proximal or distal to the FISH probes, and does not provide any information about the length of the deletion. In order to increase the detection rate of 22q11.2 deletion and to better characterize the size and position of such deletions we undertook a study of 22q11.2 cases using multiplex ligation dependent probe amplification (MLPA). We used MLPA to estimate the size of the 22q11.2 deletions in 51 patients positive for TUPLE1 or N25 (FISH) testing, and to investigate 12 patients with clinical features suggestive of 22q11DS and negative FISH results. MLPA analysis confirmed a microdeletion in all 51 FISH-positive samples as well as microduplications in three samples. Further, it allowed us to delineate deletions not previously detected using standard clinical FISH probes in 2 of 12 subjects with clinical features suggestive of 22q11DS. We conclude that MLPA is a cost-effective and accurate diagnostic tool for 22q11DS with a higher sensitivity than FISH alone. Additional advantages of MLPA testing in our study included determination of deletion length and detection of 22q11.2 duplications. (c) 2007 Wiley-Liss, Inc.
  American Journal of Medical Genetics Part A 01/2008; 143A(24):2924-30. · 2.39 Impact Factor
• Article: Severe presentation of Beckwith-Wiedemann syndrome associated with high levels of constitutional paternal uniparental disomy for chromosome 11p15.

  Adam C Smith, Cheryl Shuman, David Chitayat, Leslie Steele, Peter N Ray, Jaqueline Bourgeois, Rosanna Weksberg
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  ABSTRACT: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by macrosomia, macroglossia, omphalocele, hemihyperplasia, and increased tumor risk. BWS can be associated with genetic and/or epigenetic alterations that modify imprinted gene expression on chromosome 11p15.5. Somatic mosaicism for paternal uniparental disomy (UPD) of chromosome 11p15, found in 20% of BWS patients, is associated with specific features of BWS including hemihyperplasia, Wilms tumor, and hepatoblastoma. The highly variable phenotypic spectrum of BWS associated with UPD may well reflect the level of UPD 11 cells in specific organs and tissues such that very high levels of UPD might produce a more severe phenotypic expression of BWS. In this regard we report on two patients with severe presentations of BWS and extremely high levels of UPD in DNA from lymphocytes. Clinically, both patients demonstrated extreme macroglossia, persistent hypoglycemia, cardiomyopathy, hemihyperplasia, renal abnormalities, abdominal organomegaly, hepatoblastoma and died in the first 6 months of life. These two patients support the hypothesis that high levels of UPD define high expressivity in BWS.
  American Journal of Medical Genetics Part A 01/2008; 143A(24):3010-5. · 2.39 Impact Factor
• Article: Grandpa and I have dystrophinopathy?: approach to asymptomatic hyperCKemia.

  Montri Saengpattrachai, Peter N Ray, Cynthia E Hawkins, Alan Berzen, Brenda L Banwell
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  ABSTRACT: This report describes three males from a single kinship, ages 7, 8, and 67 years with clinically asymptomatic dystrophinopathy. The index case was an 8-year-old male evaluated for asymptomatic but persistently elevated serum creatine kinase levels. Muscle biopsy demonstrated a mild myopathy, without necrotic fibers. Immunostaining for dystrophin revealed a slight reduction in sarcolemmal reactivity for the amino terminus of dystrophin. Dystrophin gene analysis revealed a deletion of exon 45 to exon 51. Genetic analysis identified two other affected males (age 7 years and 67 years), as well as four female carriers in the same family. The 7-year-old male had mildly increased creatine kinase levels with normal muscle strength. The 67-year-old grandfather had normal neuromuscular examination and serum creatine kinase levels. Asymptomatic dystrophinopathy in late adulthood is exceptionally rare, and highlights the importance of consideration of dystrophin mutation analysis in patients with hyperCKemia, even in the absence of muscle weakness.
  Pediatric Neurology 09/2006; 35(2):145-9. · 1.52 Impact Factor
• Article: Constitutional UPD for chromosome 11p15 in individuals with isolated hemihyperplasia is associated with high tumor risk and occurs following assisted reproductive technologies.

  Cheryl Shuman, Adam C Smith, Leslie Steele, Peter N Ray, Carol Clericuzio, Elaine Zackai, Melissa A Parisi, Anna T Meadows, Thaddeus Kelly, David Tichauer, Jeremy A Squire, Paul Sadowski, Rosanna Weksberg
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  ABSTRACT: Isolated hemihyperplasia (IH) refers to a distinct diagnosis involving asymmetric overgrowth of single or multiple organs or regions of the body and can result from various genomic changes including molecular alterations of 11p15; these are paternal uniparental disomy (UPD), and alterations of methylation at two imprinting centers at 11p15: IC1 (H19) and IC2 (KCNQ1OT1). As little information is available on the molecular basis of tumor development in IH, or on the frequency of tumors in children with different molecular subtypes of IH, molecular testing was undertaken on 51 patients with IH and revealed: 8 (16%) with UPD, 3 (6%) with hypomethylation at KCNQ1OT1, and 0 with hypermethylation at H19. Of the 8 patients with UPD, 4 had tumors (3 hepatoblastomas, 1 Wilms tumor); 0/3 patients with hypomethylation at KCNQ1OT1 had a tumor; of the remaining 40 with no molecular alterations, 6 had tumors (3 Wilms tumors, 2 neuroblastomas, 1 adrenocortical adenoma). The 50% tumor frequency in patients with IH and UPD was statistically significantly higher than the 15% tumor frequency in those with IH and no molecular alteration detected (Fisher's exact test P = 0.047, OR 5.67). This is the first demonstration that UPD at 11p15 in patients with IH confers a higher tumor risk than in patients with IH without this molecular change. Of note, two of the eight patients with UPD and IH were conceived using assisted reproductive technologies (ART), thus raising the question whether ART might impact the rate of somatic recombination during embryonic development.
  American Journal of Medical Genetics Part A 08/2006; 140(14):1497-503. · 2.39 Impact Factor
• Article: Strategy for comprehensive molecular testing for Duchenne and Becker muscular dystrophies.

  Tracy L Stockley, Sarah Akber, Natalie Bulgin, Peter N Ray
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  ABSTRACT: Comprehensive molecular testing for mutations in the DMD gene causing Duchenne and Becker muscular dystrophy (DMD/BMD) is challenging because of the large size of the gene and the variety of mutation types. There is an increasing demand for comprehensive DMD gene molecular testing, including deletion/duplication testing of 79 exons and direct sequencing of the 14-kb coding region from genomic DNA, to provide confirmation of clinical diagnoses in affected patients and to determine carrier risk for family members. To determine an efficient strategy to prioritize patients for comprehensive molecular testing of the DMD gene, we tested a consecutive cohort of 165 males referred over a 4-year period because of a suspicion of DMD or BMD using: (1) a new quantitative multiplex polymerase chain reaction (PCR) assay designed to detect deletions or duplications in all exons of the gene and the brain promoter and (2) direct sequencing of the coding region and intron/exon boundaries. For the patients being tested because of a suspicion of DMD, deletion/duplication testing followed by direct sequencing detected pathogenic mutations in 98% (106/108 total patients). However, of the patients tested because of a suspicion of BMD, only 60% (34/57 total patients) had causative mutations identified, all of which were deletions or duplications. Our results suggest that direct genomic sequence analysis of the DMD gene is a useful addition to deletion/duplication testing for diagnosis of DMD, but does not provide an improved sensitivity compared to deletion/duplication analysis alone for the diagnosis of BMD. In addition, due to the relatively common finding of single exon deletions and duplications (22%, 27 of 125 total patients with deletions/duplications), methods to examine all exons of the gene for deletions/duplications should be used as the initial molecular quantitative test for DMD and BMD.
  Genetic Testing 02/2006; 10(4):229-43. · 1.17 Impact Factor
• Article: The cystic fibrosis transmembrane conductance regulator gene and ion channel function in patients with idiopathic pancreatitis.

  Michele D Bishop, Steven D Freedman, Julian Zielenski, Najma Ahmed, Annie Dupuis, Sheelagh Martin, Lynda Ellis, Julie Shea, Isobel Hopper, Mary Corey, Paul Kortan, Gregory Haber, Christine Ross, John Tzountzouris, Leslie Steele, Peter N Ray, Lap-Chee Tsui, Peter R Durie
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  ABSTRACT: Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations are associated with cystic fibrosis (CF)-related monosymptomatic conditions, including idiopathic pancreatitis. We evaluated prospectively enrolled patients who had idiopathic recurrent acute pancreatitis or idiopathic chronic pancreatitis, healthy controls, CF heterozygotes, and CF patients (pancreatic insufficient or sufficient) for evidence of CFTR gene mutations and abnormalities of ion transport by sweat chloride and nasal potential difference testing. DNA samples from anonymous blood donors were controls for genotyping. At least one CFTR mutation or variant was carried in 18 of 40 patients (45%) with idiopathic chronic pancreatitis and in 6 of 16 patients (38%) with idiopathic recurrent acute pancreatitis but in only 11 of the 50 controls (22%, P=0.005). Most identified mutations were rare and would not be identified in routine genetic screening. CFTR mutations were identified on both alleles in six patient (11%). Ion transport measurements in patients with pancreatitis showed a wide range of results, from the values in patients with classically diagnosed CF to those in the obligate heterozygotes and healthy controls. In general, ion channel measurements correlated with the number and severity of CFTR mutations. Twelve of 56 patients with pancreatitis (21%) fulfilled current clinical criteria for the diagnosis of CF, but CFTR genotyping alone confirmed the diagnosis in only two of these patients. We concluded that extensive genotyping and ion channel testing are useful to confirm or exclude the diagnosis of CF in the majority of patients with idiopathic pancreatitis.
  Human Genetics 01/2006; 118(3-4):372-81. · 5.07 Impact Factor
• Article: Analysis of the glucocerebrosidase gene in Parkinson's disease.

  Christine Sato, Angharad Morgan, Anthony E Lang, Shabnam Salehi-Rad, Toshitaka Kawarai, Yan Meng, Peter N Ray, Lindsay A Farrer, Peter St George-Hyslop, Ekaterina Rogaeva
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  ABSTRACT: Parkinson's disease (PD) is a common progressive neurodegenerative disorder characterized clinically by a combination of motor symptoms. Identifying novel PD genetic risk factors is important for understanding its pathogenesis. A recent study suggested that up to 21% of subjects with PD may have mutations in the glucocerebrosidase (GBA) gene. We investigated the GBA gene for mutations in 88 PD cases and 122 normal controls and detected the presence of heterozygous GBA mutations in 5 PD cases and in 1 control. Sequencing of the entire open reading frame of the GBA gene in a subset of 25 cases with early-onset PD (<50 years of age) uncovered no additional mutations. Our results demonstrate a marginally significant association of GBA mutations with PD and suggest that variations in the GBA gene may constitute a rare susceptibility factor for PD (P = 0.048).
  Movement Disorders 04/2005; 20(3):367-70. · 4.51 Impact Factor
• Article: Canavan disease: carrier-frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay.

  Annette Feigenbaum, Robert Moore, Joe Clarke, Stacy Hewson, David Chitayat, Peter N Ray, Tracy L Stockley
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  ABSTRACT: Canavan disease (CD) is an autosomal recessive progressive neurodegenerative disorder prevalent in the Ashkenazi Jewish (AJ) population. The carrier rate for the most common mutations that cause CD in the AJ population is often quoted as 1:37-1:40. This is not supported by our finding of only two diagnosed cases of CD in the last 20 years in the Toronto AJ population of 160,000 and an estimated birth rate of 1,500-2,000 per year. Therefore, we embarked on a prevalence cross-sectional screening study to determine the carrier rate of CD in this population. In order to perform low-cost, high-throughput population testing for CD using molecular techniques, we first developed a novel molecular assay using multiplex fluorescent allele specific polymerase chain reaction (PCR) to test for the three most common mutations causing CD in the AJ population (A854C, C693A, C914A) and a neutral polymorphism at the site of the C693A mutation. During testing it was noted that individuals who were carriers of the A854C mutation also had a T polymorphism at the site of the C693A mutation (Y231X). We confirmed that in all A854C carriers the 854C mutation was in disequilibrium with the 693T polymorphism, indicating a founder chromosome for the A854C mutation in the AJ population. Twenty-five carriers were found from 1,423 samples yielding a carrier rate of 1:57, differing from the widely quoted frequency of 1:40 and supporting our observed frequency of disease.
  American Journal of Medical Genetics Part A 02/2004; 124A(2):142-7. · 2.39 Impact Factor
• Article: Screening of patients with craniosynostosis: molecular strategy.

  Kathy Chun, Ahmad S Teebi, Cyrus Azimi, Leslie Steele, Peter N Ray
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  ABSTRACT: Craniosynostosis is the premature fusion of calvarial bones leading to an abnormal head shape. The craniosynostosis syndromes are clinically heterogeneous with overlapping features, which make an accurate diagnosis difficult at times. Although the clarification of a genetic lesion does not have a direct impact on patient management in many cases, there is a significant benefit in providing accurate prenatal diagnosis. Genetic counsellors are also able to offer better risk estimates of recurrences to non-manifesting carriers and their extended family members and for affected patients of reproductive age. Advances in gene discovery have shown that craniosynostosis syndromes delineated on clinical bases, with the possible exception of Apert syndrome, are genetically heterogeneous, and mutations have been found in fibroblast growth factor receptors (FGFR) 1, 2, 3 and TWIST. We surveyed 99 craniosynostosis patients at the molecular level and found mutations in 50 of them. Six novel point mutations were identified: three in FGFR2 and three in TWIST. Two Saethre-Chotzen patients with TWIST microdeletions at 7p21 were also found. The other mutations identified have been previously reported. In studying these 99 patients, we developed a diagnostic strategy for craniosynostosis testing, where sequential analysis of recurrent mutations was followed by selective sequencing. This algorithm makes testing of craniosynostosis disorders more efficient and cost-effective.
  American Journal of Medical Genetics Part A 09/2003; 120A(4):470-3. · 2.39 Impact Factor