Publications by authors named "Matthew Pastore"

26 Publications

  • Page 1 of 1

Lessons learned from 40 novel PIGA patients and a review of the literature.

Epilepsia 2020 06 26;61(6):1142-1155. Epub 2020 May 26.

Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.

Objective: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations.

Methods: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches.

Results: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein.

Significance: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.
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http://dx.doi.org/10.1111/epi.16545DOI Listing
June 2020

Characterization of the renal phenotype in RMND1-related mitochondrial disease.

Mol Genet Genomic Med 2019 12 30;7(12):e973. Epub 2019 Sep 30.

Texas Children's Hospital, Houston, TX, USA.

Background: The nuclear encoded gene RMND1 (Required for Meiotic Nuclear Division 1 homolog) has recently been linked to RMND1-related mitochondrial disease (RRMD). This autosomal recessive condition characteristically presents with an infantile-onset multisystem disease characterized by severe hypotonia, global developmental delay, failure to thrive, sensorineural hearing loss, and lactic acidosis. Renal disease, however, appears to be one of the more prominent features of RRMD, affecting patients at significantly higher numbers compared to other mitochondrial diseases. We report the clinical, histological, and molecular findings of four RRMD patients across three academic institutions with a focus on the renal manifestations.

Methods: Four patients were identified for the purpose of this study, all of whom had molecular confirmation at the time of inclusion, which included the common pathogenic variant c.713A>G (p.N238S) as well as the three rare variants: c.485delC (p.P162fs), c.533C>T (p.T178M), and c.1317 + 1G>C splice donor variant. Medical history and laboratory findings were collected from the medical records and medical providers.

Results: In this study, all four patients developed renal disease characterized as tubulopathy (3/4), renal tubular acidosis (2/4), interstitial nephritis (1/4), and/or end-stage renal disease (4/4) necessitating renal transplantation (2/4). Histological evaluation of renal biopsy specimens revealed generalized tubular atrophy and on electron microscopy, abundant mitochondria with pleomorphism and abnormal cristae.

Conclusion: Our experience with RRMD demonstrates a specific pattern of renal disease manifestations and clinical course. Patients are unlikely to respond to traditional chronic kidney disease (CKD) treatments, making early diagnosis and consideration of renal transplantation paramount to the management of RRMD.
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http://dx.doi.org/10.1002/mgg3.973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900359PMC
December 2019

Correction: Variants in MED12L, encoding a subunit of the Mediator kinase module, are responsible for intellectual disability associated with transcriptional defect.

Genet Med 2019 11;21(11):2663

CHU Nantes, Service de Génétique Médicale, Nantes, France.

In the Acknowledgements section of the paper the authors neglected to mention that the study was supported by a grant from the National Human Genome Research Institute (NHGRI) UM1HG007301 (S.H., M.L.T.). In addition, the award of MD was associated with the authors Michelle L. Thompson and Susan Hiatt instead of PhD. The PDF and HTML versions of the Article have been modified accordingly.
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http://dx.doi.org/10.1038/s41436-019-0590-2DOI Listing
November 2019

Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect.

Genet Med 2019 12 3;21(12):2713-2722. Epub 2019 Jun 3.

CHU Nantes, Service de Génétique Médicale, Nantes, France.

Purpose: Mediator is a multiprotein complex that allows the transfer of genetic information from DNA binding proteins to the RNA polymerase II during transcription initiation. MED12L is a subunit of the kinase module, which is one of the four subcomplexes of the mediator complex. Other subunits of the kinase module have been already implicated in intellectual disability, namely MED12, MED13L, MED13, and CDK19.

Methods: We describe an international cohort of seven affected individuals harboring variants involving MED12L identified by array CGH, exome or genome sequencing.

Results: All affected individuals presented with intellectual disability and/or developmental delay, including speech impairment. Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features. Three individuals had a MED12L deletion or duplication. The other four individuals harbored single-nucleotide variants (one nonsense, one frameshift, and two splicing variants). Functional analysis confirmed a moderate and significant alteration of RNA synthesis in two individuals.

Conclusion: Overall data suggest that MED12L haploinsufficiency is responsible for intellectual disability and transcriptional defect. Our findings confirm that the integrity of this kinase module is a critical factor for neurological development.
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http://dx.doi.org/10.1038/s41436-019-0557-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243155PMC
December 2019

Correction to: De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome.

Genome Med 2019 03 25;11(1):16. Epub 2019 Mar 25.

Baylor Genetics, Houston, TX, 77021, USA.

It was highlighted that the original article [1] contained a typographical error in the Results section. Subject 17 was incorrectly cited as Subject 1. This Correction article shows the revised statement. The original article has been updated.
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http://dx.doi.org/10.1186/s13073-019-0630-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434874PMC
March 2019

De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome.

Genome Med 2019 02 28;11(1):12. Epub 2019 Feb 28.

Baylor Genetics, Houston, TX, 77021, USA.

Background: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity).

Methods: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes.

Results: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances.

Conclusions: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.
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http://dx.doi.org/10.1186/s13073-019-0623-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393995PMC
February 2019

Diagnostic Utility of Whole Exome Sequencing in the Neuromuscular Clinic.

Neuropediatrics 2019 04 21;50(2):96-102. Epub 2019 Jan 21.

Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, United States.

Next-generation sequencing is a powerful diagnostic tool, yet it has proven inadequate to establish a diagnosis in all cases of congenital hypotonia or childhood onset weakness. We sought to describe the impact of whole exome sequencing (WES), which has only recently become widely available clinically, on molecular diagnosis in the Nationwide Children's Hospital Neuromuscular clinics. We reviewed records of all patients in our clinic with pediatric onset of symptoms who had WES done since 2013. Patients were included if clinical suspicion was high for a neuromuscular disease. Clinical WES was performed in 30 families, representing 31 patients, all of whom were seen for hypotonia, weakness, or gait disturbance. Probands had between 2 and 12 genetic diagnostic tests prior to obtaining WES. A genetic diagnosis was established in 11 families (37%), and in 12 patients (39%), with mutations in 10 different genes. Five of these genes have only been associated with disease since 2013, and were not previously represented on clinically available disease gene panels. Our results confirm the utility of WES in the clinical setting, particularly for genetically heterogeneous syndromes. The availability of WES can provide an end to the diagnostic odyssey for parents and allow for expansion of phenotypes.
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http://dx.doi.org/10.1055/s-0039-1677734DOI Listing
April 2019

Transferring Exome Sequencing Data from Clinical Laboratories to Healthcare Providers: Lessons Learned at a Pediatric Hospital.

Front Genet 2018 21;9:54. Epub 2018 Feb 21.

Research Information Solutions and Innovation, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.

The adoption rate of genome sequencing for clinical diagnostics has been steadily increasing leading to the possibility of improvement in diagnostic yields. Although laboratories generate a summary clinical report, sharing raw genomic data with healthcare providers is equally important, both for secondary research studies as well as for a deeper analysis of the data itself, as seen by the efforts from organizations such as American College of Medical Genetics and Genomics and Global Alliance for Genomics and Health. Here, we aim to describe the existing protocol of genomic data sharing between a certified clinical laboratory and a healthcare provider and highlight some of the lessons learned. This study tracked and subsequently evaluated the data transfer workflow for 19 patients, all of whom consented to be part of this research study and visited the genetics clinic at a tertiary pediatric hospital between April 2016 to December 2016. Two of the most noticeable elements observed through this study are the manual validation steps and the discrepancies in patient identifiers used by a clinical lab vs. healthcare provider. Both of these add complexity to the transfer process as well as make it more susceptible to errors. The results from this study highlight some of the critical changes that need to be made in order to improve genomic data sharing workflows between healthcare providers and clinical sequencing laboratories.
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http://dx.doi.org/10.3389/fgene.2018.00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826334PMC
February 2018

Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.

PLoS Genet 2017 Jul 24;13(7):e1006905. Epub 2017 Jul 24.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States of America.

Dominant mutations in CACNA1A, encoding the α-1A subunit of the neuronal P/Q type voltage-dependent Ca2+ channel, can cause diverse neurological phenotypes. Rare cases of markedly severe early onset developmental delay and congenital ataxia can be due to de novo CACNA1A missense alleles, with variants affecting the S4 transmembrane segments of the channel, some of which are reported to be loss-of-function. Exome sequencing in five individuals with severe early onset ataxia identified one novel variant (p.R1673P), in a girl with global developmental delay and progressive cerebellar atrophy, and a recurrent, de novo p.R1664Q variant, in four individuals with global developmental delay, hypotonia, and ophthalmologic abnormalities. Given the severity of these phenotypes we explored their functional impact in Drosophila. We previously generated null and partial loss-of-function alleles of cac, the homolog of CACNA1A in Drosophila. Here, we created transgenic wild type and mutant genomic rescue constructs with the two noted conserved point mutations. The p.R1673P mutant failed to rescue cac lethality, displayed a gain-of-function phenotype in electroretinograms (ERG) recorded from mutant clones, and evolved a neurodegenerative phenotype in aging flies, based on ERGs and transmission electron microscopy. In contrast, the p.R1664Q variant exhibited loss of function and failed to develop a neurodegenerative phenotype. Hence, the novel R1673P allele produces neurodegenerative phenotypes in flies and human, likely due to a toxic gain of function.
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http://dx.doi.org/10.1371/journal.pgen.1006905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557584PMC
July 2017

Role of CFTR mutation analysis in the diagnostic algorithm for cystic fibrosis.

World J Pediatr 2017 Apr 15;13(2):129-135. Epub 2017 Feb 15.

Department of Pediatrics, the Ohio State University College of Medicine, Columbus, Ohio, USA.

Background: The cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation identification is being used with increased frequency to aid in the diagnosis of cystic fibrosis (CF) in those suspected with CF. Aim of this study was to identify diagnostic outcomes when CFTR mutational analysis was used in CF diagnosis. CFTR mutational analysis results were also compared with sweat chloride results.

Methods: This study was done on all patients at our institution who had CFTR mutation analysis over a sevenyear period since August 2006.

Results: A total of 315 patients underwent CFTR mutational analysis. Fifty-one (16.2%) patients had two mutations identified. Among them 32 had positive sweat chloride levels (≥60 mmol/L), while seven had borderline sweat chloride levels (40-59 mmol/L). An additional 70 patients (22.3%) had only one mutation identified. Among them eight had positive sweat chloride levels, and 17 had borderline sweat chloride levels. Fifty-five patients (17.5%) without CFTR mutations had either borderline (n=45) or positive (n=10) sweat chloride results. Three patients with a CF phenotype had negative CFTR analysis but elevated sweat chloride levels. In eighty-three patients (26.4%) CFTR mutational analysis was done without corresponding sweat chloride testing.

Conclusions: Although CFTR mutation analysis has improved the diagnostic capability for CF, its use either as the first step or the only test to diagnose CFTR dysfunction should be discouraged and CF diagnostic guidelines need to be followed.
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http://dx.doi.org/10.1007/s12519-017-0015-8DOI Listing
April 2017

SRD5A3-CDG: Expanding the phenotype of a congenital disorder of glycosylation with emphasis on adult onset features.

Am J Med Genet A 2016 12 2;170(12):3165-3171. Epub 2016 Aug 2.

Human Genetics Program, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, California.

Increasing numbers of congenital disorders of glycosylation (CDG) have been reported recently resulting in an expansion of the phenotypes associated with this group of disorders. SRD5A3 codes for polyprenol reductase which converts polyprenol to dolichol. This is a major pathway for dolichol biosynthesis for N-glycosylation, O-mannosylation, C-mannosylation, and GPI anchor synthesis. We present the features of five individuals (three children and two adults) with mutations in SRD5A3 focusing on the variable eye and skin involvement. We compare that to 13 affected individuals from the literature including five adults allowing us to delineate the features that may develop over time with this disorder including kyphosis, retinitis pigmentosa, and cataracts. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115938PMC
December 2016

Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome.

Am J Hum Genet 2014 Nov 16;95(5):579-83. Epub 2014 Oct 16.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Whole Genome Laboratory, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three genes. We describe 11 individuals with clinical features of 5q31.3 microdeletion syndrome and de novo mutations in PURA, encoding transcriptional activator protein Pur-α, within the critical region. These data implicate causative PURA mutations responsible for the severe neurological phenotypes observed in this syndrome.
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http://dx.doi.org/10.1016/j.ajhg.2014.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225583PMC
November 2014

De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum.

Hum Genet 2015 Jan 19;134(1):97-109. Epub 2014 Oct 19.

Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany,

Recently, de novo heterozygous loss-of-function mutations in beta-catenin (CTNNB1) were described for the first time in four individuals with intellectual disability (ID), microcephaly, limited speech and (progressive) spasticity, and functional consequences of CTNNB1 deficiency were characterized in a mouse model. Beta-catenin is a key downstream component of the canonical Wnt signaling pathway. Somatic gain-of-function mutations have already been found in various tumor types, whereas germline loss-of-function mutations in animal models have been shown to influence neuronal development and maturation. We report on 16 additional individuals from 15 families in whom we newly identified de novo loss-of-function CTNNB1 mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion). All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity). The craniofacial phenotype comprised microcephaly (typically -2 to -4 SD) in 12 of 16 and some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion). With this detailed phenotypic characterization of 16 additional individuals, we expand and further establish the clinical and mutational spectrum of inactivating CTNNB1 mutations and thereby clinically delineate this new CTNNB1 haploinsufficiency syndrome.
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http://dx.doi.org/10.1007/s00439-014-1498-1DOI Listing
January 2015

MCPH1 deletion in a newborn with severe microcephaly and premature chromosome condensation.

Eur J Med Genet 2013 Nov 27;56(11):609-13. Epub 2013 Sep 27.

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.

A newborn with severe microcephaly and a history of parental consanguinity was referred for cytogenetic analysis and subsequently for genetic evaluation. While a 46,XY karyotype was eventually obtained, premature chromosome condensation was observed. A head MRI confirmed primary microcephaly. This combination of features focused clinical interest on the MCPH1 gene and directed genetic testing by sequence analysis and duplication/deletion studies disclosed a homozygous deletion of exons 1-11 of the MCPH1 gene. This case illustrates a strength of standard cytogenetic evaluation in directing molecular testing to a single target gene in this disorder, allowing much more rapid diagnosis at a substantial cost savings for this family.
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http://dx.doi.org/10.1016/j.ejmg.2013.09.007DOI Listing
November 2013

Neurodevelopmental disorders among individuals with duplication of 4p13 to 4p12 containing a GABAA receptor subunit gene cluster.

Eur J Hum Genet 2014 Jan 22;22(1):105-9. Epub 2013 May 22.

1] Division of Molecular and Human Genetics, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA [2] Department of Pediatrics, The Ohio State University, Columbus, OH, USA [3] Center for Cardiovascular and Pulmonary Research, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.

Recent studies have shown that certain copy number variations (CNV) are associated with a wide range of neurodevelopmental disorders, including autism spectrum disorders (ASD), bipolar disorder and intellectual disabilities. Implicated regions and genes have comprised a variety of post synaptic complex proteins and neurotransmitter receptors, including gamma-amino butyric acid A (GABAA). Clusters of GABAA receptor subunit genes are found on chromosomes 4p12, 5q34, 6q15 and 15q11-13. Maternally inherited 15q11-13 duplications among individuals with neurodevelopmental disorders are well described, but few case reports exist for the other regions. We describe a family with a 2.42 Mb duplication at chromosome 4p13 to 4p12, identified in the index case and other family members by oligonucleotide array comparative genomic hybridization, that contains 13 genes including a cluster of four GABAA receptor subunit genes. Fluorescent in-situ hybridization was used to confirm the duplication. The duplication segregates with a variety of neurodevelopmental disorders in this family, including ASD (index case), developmental delay, dyspraxia and ADHD (brother), global developmental delays (brother), learning disabilities (mother) and bipolar disorder (maternal grandmother). In addition, we identified and describe another individual unrelated to this family, with a similar duplication, who was diagnosed with ASD, ADHD and borderline intellectual disability. The 4p13 to 4p12 duplication appears to confer a susceptibility to a variety of neurodevelopmental disorders in these two families. We hypothesize that the duplication acts through a dosage effect of GABAA receptor subunit genes, adding evidence for alterations in the GABAergic system in the etiology of neurodevelopmental disorders.
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http://dx.doi.org/10.1038/ejhg.2013.99DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865421PMC
January 2014

Detailed clinical, genetic and neuroimaging characterization of OFD VI syndrome.

Eur J Med Genet 2013 Jun 21;56(6):301-8. Epub 2013 Mar 21.

Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Grand-Est, Hôpital d'Enfants, CHU Dijon, France.

Oral-facial-digital syndrome type VI (OFD VI) is characterized by the association of malformations of the face, oral cavity and extremities, distinguished from the 12 other OFD syndromes by cerebellar and metacarpal abnormalities. Cerebellar malformations in OFD VI have been described as a molar tooth sign (MTS), thus, including OFD VI among the "Joubert syndrome related disorders" (JSRD). OFD VI diagnostic criteria have recently been suggested: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of hands or feet; 3) hypothalamic hamartoma. In order to further delineate this rare entity, we present the neurological and radiological data of 6 additional OFD VI patients. All patients presented oral malformations, facial dysmorphism and distal abnormalities including frequent polydactyly (66%), as well as neurological symptoms with moderate to severe mental retardation. Contrary to historically reported patients, mesoaxial polydactyly did not appear to be a predominant clinical feature in OFD VI. Sequencing analyzes of the 14 genes implicated in JSRD up to 2011 revealed only an OFD1 frameshift mutation in one female OFD VI patient, strengthening the link between these two oral-facial-digital syndromes and JSRD.
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http://dx.doi.org/10.1016/j.ejmg.2013.03.004DOI Listing
June 2013

Coronary artery disease in a Werner syndrome-like form of progeria characterized by low levels of progerin, a splice variant of lamin A.

Am J Med Genet A 2011 Dec 7;155A(12):3002-6. Epub 2011 Nov 7.

Medicine, University of Washington, Seattle, Washington 98195-7470, USA.

Classical Hutchinson-Gilford progeria syndrome (HGPS) is caused by LMNA mutations that generate an alternatively spliced form of lamin A, termed progerin. HGPS patients present in early childhood with atherosclerosis and striking features of accelerated aging. We report on two pedigrees of adult-onset coronary artery disease with progeroid features, who were referred to our International Registry of Werner Syndrome (WS) because of clinical features consistent with the diagnosis. No mutations were identified in the WRN gene that is responsible for WS, among these patients. Instead, we found two novel heterozygous mutations at the junction of exon 10 and intron 11 of the LMNA gene. These mutations resulted in the production of progerin at a level substantially lower than that of HGPS. Our findings indicate that LMNA mutations may result in coronary artery disease presenting in the fourth to sixth decades along with short stature and a progeroid appearance resembling WS. The absence of early-onset cataracts in this setting should suggest the diagnosis of progeroid laminopathy. This study illustrates the evolving genotype-phenotype relationship between the amount of progerin produced and the age of onset among the spectrum of restrictive dermopathy, HGPS, and atypical forms of WS.
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http://dx.doi.org/10.1002/ajmg.a.34336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679285PMC
December 2011

A novel exon duplication of the cystic fibrosis transmembrane conductance regulator in a patient presenting with adult-onset recurrent pancreatitis.

Pancreas 2011 Jul;40(5):773-7

Sections of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA.

Pancreatitis is a rare occurrence in patients with cystic fibrosis (CF) affecting 1.2% of all patients, but it can be the first presenting sign in approximately 15% of adults with pancreatic sufficiency and a milder CF phenotype. We report a case of a woman with recurrent pancreatitis who has one cystic fibrosis-causing mutation (G551D) and the first known description of a pathologic duplication of exon 19 of the CF transmembrane conductance regulator (CFTR). A 30-year-old white woman with 30 attacks of pancreatitis over a 5-year period starting at age 25 presented to the genetics department. She was found to have a mutation in the SPINK1 gene, IVS3+184T>A, and one cystic fibrosis-causing mutation (G551D) prompting full gene sequencing of the CFTR, revealing an additional duplication of exon 19. Sweat chloride testing was elevated at 97 and 106 mmol/L. Despite normal growth parameters and lung function, it is important to be aware of recurrent pancreatitis as a presenting sign of CF. Comprehensive CF gene analysis is necessary to detect a second CF-causing mutation that may put patients at risk for more severe symptoms of pancreatitis. There is a significant difference in the prevalence of heterozygote mutations between available testing methods.
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http://dx.doi.org/10.1097/MPA.0b013e3182156e47DOI Listing
July 2011

Unexpected detection of dystrophin gene deletions by array comparative genomic hybridization.

Am J Med Genet A 2010 Sep;152A(9):2301-7

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA.

Array comparative genomic hybridization has increasingly become the standard of care to evaluate patients for genomic imbalance. As the patient population evaluated by microarray expands, there is certain to be an increase in the detection of unexpected, yet common diseases. When array results predict a late-onset disorder or cancer predisposition, it becomes a challenge for physicians and counselors to adequately address with patients. Included in this study were three patients described with nonspecific phenotypic findings who underwent microarray testing to better define their disease etiology. An unexpected deletion within the dystrophin gene was observed in each case, despite that no patient was suspected of a dystrophinopathy at the time of testing. The patients included an 8-day-old male with a dystrophin deletion predictive of Becker muscular dystrophy, an 18-month old female found to be the carrier of deletion, and a 4-year-8-month-old male with a deletion predictive of Duchenne muscular dystrophy. In this circumstance it becomes difficult to counsel the family, as well as to predict disease course when underlying medical conditions may exist. However, early detection may enable the patient to receive proactive treatment, and allows for screening of at-risk family members. Ultimately, it is up to the clinician to promote informed decision-making within the family prior to testing, and ensure that adequate counseling is provided during follow-up.
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http://dx.doi.org/10.1002/ajmg.a.33532DOI Listing
September 2010

Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly.

Autism Res 2010 Jun;3(3):137-41

Center for Molecular and Human Genetics, Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205, USA.

There is a strong genetic component to autism spectrum disorders (ASD), but due to significant genetic heterogeneity, individual genetic abnormalities contribute a small percentage to the overall total. Previous studies have demonstrated PTEN mutations in a sizable proportion of individuals with ASD or mental retardation/developmental delays (MR/DD) and macrocephaly that do not have features of Cowden or Bannayan-Riley-Ruvalcaba syndrome. This study was performed to confirm our previous results. We reviewed the charts of individuals who had PTEN clinical sequencing performed at our institution from January 2008 to July 2009. There were 93 subjects tested from our institution during that period. PTEN mutations were found in 2/39 (5.1%) ASD patients and 2/51 (3.9%) MR/DD patients. Three additional patients without mutations had no diagnostic information. Multiple relatives of individuals with a PTEN mutation had macrocephaly, MR, or early onset cancer (breast, renal, and prostate). Of those relatives tested, all had the familial PTEN mutation. None of the affected relatives had previously been diagnosed with Cowden or Bannayan-Riley-Ruvalcaba syndrome. We noted in our previous study several adult relatives without any findings who carried a mutation. Combined with data from our previous cohort, we have found PTEN mutations in 7/99 (7.1%) of individuals with ASD and 8/100 (8.0%) of individuals with MR/DD, all of whom had macrocephaly. We recommend testing for mutations in PTEN for individuals with ASD or MR/DD and macrocephaly. If mutations are found, other family members should be offered testing and the adults offered cancer screening if they have a PTEN mutation.
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http://dx.doi.org/10.1002/aur.132DOI Listing
June 2010

A tale of two deletions: a report of two novel 20p13 --> pter deletions.

Am J Med Genet A 2010 Apr;152A(4):1000-7

Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202-5251, USA.

We report on two patients with 1.7 and 1.2 Mb terminal 20p deletions, which have apparently not been reported previously. Both individuals exhibit certain similar features including large fontanelles, ear abnormalities, and seizures. However, even though the deletions are of similar size, there were many disparate features between the two. The deletions in each patient encompass at least 28 genes that may provide useful candidates for ear development and cranial ossification.
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http://dx.doi.org/10.1002/ajmg.a.33339DOI Listing
April 2010

The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly.

Genet Med 2009 Feb;11(2):111-7

Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205, USA.

Purpose: To define the prevalence of PTEN mutations in a clinical cohort of pediatric subjects with autism spectrum disorders (ASDs), developmental delay/mental retardation (DD/MR), and/or macrocephaly and to assess genotype-phenotype correlations.

Methods: Medical records of patients who had clinical PTEN gene sequencing ordered through our institution between January 1, 2005 and December 31, 2007 were abstracted to confirm genetic test results and medical diagnoses. Phenotypic information related to the diagnoses, prenatal history, early developmental milestones, physical characteristics, and family history for those with a confirmed PTEN mutation was also recorded.

Results: One hundred fourteen patients were tested during this time period for indications of ASDs (N = 60), DD/MR (N = 49), or macrocephaly only (N = 5). Eleven mutations were identified: five in patients with ASDs and six in those with DD/MR, resulting in a prevalence of 8.3% and 12.2% in these respective clinical populations. All individuals with a PTEN mutation had significant macrocephaly (>2.0 SD) CONCLUSIONS: These data illustrate that PTEN gene sequencing has a high diagnostic yield when performed in a selected population of individuals with ASDs or DD/MR and macrocephaly. Germline mutations in PTEN are an important, identifiable etiology among these patients.
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http://dx.doi.org/10.1097/GIM.0b013e31818fd762DOI Listing
February 2009

Genetic testing in autism: how much is enough?

Genet Med 2007 May;9(5):268-74

Center for Molecular and Human Genetics, Columbus Children's Research Institute, Columbus, Ohio 43205, USA.

Purpose: To evaluate the yield of genetic testing in children with autism spectrum disorders.

Methods: We performed a retrospective chart review of 71 unrelated patients with a diagnosis of an isolated autism spectrum disorder seen in a genetics clinic over a period of 14 months. For most, referrals occurred after evaluation by a developmental pediatrician and/or psychologist to establish the diagnosis. Tiered laboratory testing for the majority of the patients followed a guideline that was developed in collaboration with clinicians at The Autism Center at Children's Hospital, Columbus, OH.

Results: The patients included 57 males and 14 females; 57 met DSM-IV criteria for autism, with the rest being Asperger or pervasive developmental disorder not otherwise specified. Macrocephaly [head circumference (HC) >or=95%] was present in 19 (27%). Two children had visible chromosome abnormalities (47,XYY; 48,XY + 2mar/49,XY + 3mar). Two patients with autism and macrocephaly had heterozygous mutations in the PTEN tumor suppressor gene. Three females had Rett syndrome, each confirmed by DNA sequencing of the MECP2 gene. Extensive metabolic testing produced no positive results, nor did fragile X DNA testing.

Conclusion: The overall diagnostic yield was 10% (7/71). PTEN gene sequencing should be considered in any child with macrocephaly and autism or developmental delay. Metabolic screening may not be warranted in autism spectrum disorders without more specific indications or additional findings.
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http://dx.doi.org/10.1097/gim.0b013e31804d683bDOI Listing
May 2007

Increasing knowledge of PTEN germline mutations: Two additional patients with autism and macrocephaly.

Am J Med Genet A 2007 Mar;143A(6):589-93

Center for Molecular and Human Genetics, Columbus Children Research Institute, The Ohio State University, Columbus, Ohio, USA.

Recently, Butler et al. [2005; J Med Genet 42:318-321] reported the presence of heterozygous germline mutations in the PTEN tumor suppressor gene in three children with autism and macrocephaly. Here, we report the presence of PTEN mutations in two additional unrelated children with macrocephaly and autism. Our findings extend those of Butler et al. and suggest that PTEN gene sequencing should be included in the genetic evaluation of this subset of autistic individuals.
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http://dx.doi.org/10.1002/ajmg.a.31619DOI Listing
March 2007

Trisomy 16p: a longitudinal profile and photo essay.

Am J Med Genet A 2006 Jan;140(2):174-9

The Ohio State University and Children's Hospital, Columbus, Ohio 43205, USA.

As more cases of complete or partial trisomy 16p are described, a clinical picture of these patients is emerging. A specific phenotype appears to be most consistent if the band 16p13.1-16p13.3 is present in triplicate. The hallmarks of this syndrome are microcephaly, a specific facial appearance with round facies, micrognathia, and small protruding auricles, and psychomotor as well as growth retardation. We report on a patient with partial trisomy 16p due to a maternally-inherited balanced translocation between chromosomes 2q and 16p and describe the change in phenotype over 21 years, as well as the level of development achieved.
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http://dx.doi.org/10.1002/ajmg.a.31027DOI Listing
January 2006

A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy.

J Cell Biol 2003 Jan 6;160(1):41-52. Epub 2003 Jan 6.

Department of Neurology, Ohio State University, Columbus, OH 43210, USA.

5q spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and the leading genetic cause of infantile death. Patients lack a functional survival of motor neurons (SMN1) gene, but carry one or more copies of the highly homologous SMN2 gene. A homozygous knockout of the single murine Smn gene is embryonic lethal. Here we report that in the absence of the SMN2 gene, a mutant SMN A2G transgene is unable to rescue the embryonic lethality. In its presence, the A2G transgene delays the onset of motor neuron loss, resulting in mice with mild SMA. We suggest that only in the presence of low levels of full-length SMN is the A2G transgene able to form partially functional higher order SMN complexes essential for its functions. Mild SMA mice exhibit motor neuron degeneration, muscle atrophy, and abnormal EMGs. Animals homozygous for the mutant transgene are less severely affected than heterozygotes. This demonstrates the importance of SMN levels in SMA even if the protein is expressed from a mutant allele. Our mild SMA mice will be useful in (a) determining the effect of missense mutations in vivo and in motor neurons and (b) testing potential therapies in SMA.
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http://dx.doi.org/10.1083/jcb.200208079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172739PMC
January 2003