Publications by authors named "Arti Pandya"

45 Publications

Confirmation of COL4A6 variants in X-linked nonsyndromic hearing loss and its clinical implications.

Eur J Hum Genet 2021 Apr 12. Epub 2021 Apr 12.

Department of Pediatrics, Division of Genetics and Metabolism, UNC Chapel Hill, Chapel Hill, NC, USA.

Hearing loss (HL) is one of the most common sensory defects, of which X-linked nonsyndromic hearing loss (NSHL) accounts for only 1-2%. While a COL4A6 variant has been reported in a single Hungarian family with NSHL associated with inner ear malformation, causative role of COL4A6 variants and their phenotypic consequences in NSHL remain elusive. Here we report two families in which we identified a male member with X-linked HL. Each has inherited a rare hemizygous COL4A6 variant from their respective mothers, NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951 + 1 G > C. An in vitro minigene splicing assay revealed that c.951 + 1 G > T leads to skipping of exon 15, strongly suggesting a pathogenic role for this variant in the HL phenotype. The p.Gly1091Ala variant is classified as a variant of unknown significance based on the variant interpretation guidelines. This report provides evidence for variants in the COL4A6 gene resulting in X-linked NSHL. It highlights the importance of in-depth genetic studies in all family members in addition to the proband, especially in multiplex families, to determine the precise etiology of HL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-021-00881-2DOI Listing
April 2021

Cobblestone Malformation in LAMA2 Congenital Muscular Dystrophy (MDC1A).

J Neuropathol Exp Neurol 2020 09;79(9):998-1010

Department of Pathology, The University of Iowa, Iowa City, Iowa.

Congenital muscular dystrophy type 1A (MDC1A) is caused by recessive variants in laminin α2 (LAMA2). Patients have been found to have white matter signal abnormalities on magnetic resonance imaging (MRI) but rarely structural brain abnormalities. We describe the autopsy neuropathology in a 17-year-old with white matter signal abnormalities on brain MRI. Dystrophic pathology was observed in skeletal muscle, and the sural nerve manifested a mild degree of segmental demyelination and remyelination. A diffuse, bilateral cobblestone appearance, and numerous points of fusion between adjacent gyri were apparent on gross examination of the cerebrum. Brain histopathology included focal disruptions of the glia limitans associated with abnormal cerebral cortical lamination or arrested cerebellar granule cell migration. Subcortical nodular heterotopia was present within the cerebellar hemispheres. Sampling of the centrum semiovale revealed no light microscopic evidence of leukoencephalopathy. Three additional MDC1A patients were diagnosed with cobblestone malformation on brain MRI. Unlike the autopsied patient whose brain had a symmetric distribution of cobblestone pathology, the latter patients had asymmetric involvement, most severe in the occipital lobes. These cases demonstrate that cobblestone malformation may be an important manifestation of the brain pathology in MDC1A and can be present even when patients have a structurally normal brain MRI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnen/nlaa062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445049PMC
September 2020

Oculodentodigital Dysplasia: A Case Report and Major Review of the Eye and Ocular Adnexa Features of 295 Reported Cases.

Case Rep Ophthalmol Med 2020 4;2020:6535974. Epub 2020 Apr 4.

Department of Pediatrics, Division of Genetics and Metabolism, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Oculodentodigital dysplasia (ODDD) is a rare genetic disorder associated with a characteristic craniofacial profile with variable dental, limb, eye, and ocular adnexa abnormalities. We performed an extensive literature review to highlight key eye features in patients with ODDD and report a new case of a female patient with a heterozygous missense mutation (c.65G>A, p.G22E) and clinical features consistent with the condition. Our patient presented with multiple congenital anomalies including syndactyly, microphthalmia, microcornea, retrognathia, and a small nose with hypoplastic alae and prominent columella; in addition, an omphalocele defect was present, which has not been reported in previous cases. A systematic review of the published cases to date revealed 91 literature reports of 295 individuals with ODDD. There were 73 different mutations associated with these cases, of which the most common were the following missense mutations: c.605G>A (p.R202H) (11%), c.389T>C (p.I130T) (10%), and c.119C>T (p.A40V) (10%). Mutations most commonly affect the extracellular-1 and cytoplasmic-1 domains of connexin-43 (gene product of ), predominately manifesting in microphthalmia and microcornea. The syndrome appears with an approximately equal sex ratio. The most common eye features reported among all mutations were microcornea, microphthalmia, short palpebral fissures, and glaucoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/6535974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165356PMC
April 2020

Analyses of del(GJB6-D13S1830) and del(GJB6-D13S1834) deletions in a large cohort with hearing loss: Caveats to interpretation of molecular test results in multiplex families.

Mol Genet Genomic Med 2020 04 17;8(4):e1171. Epub 2020 Feb 17.

Department of Science, Technology, & Mathematics, Gallaudet University, Washington, DC, USA.

Background: Mutations involving the closely linked GJB2 and GJB6 at the DFNB1 locus are a common genetic cause of profound congenital hearing loss in many populations. In some deaf GJB2 heterozygotes, a 309 kb deletion involving the GJB6 has been found to be the cause for hearing loss when inherited in trans to a GJB2 mutation.

Methods: We screened 2,376 probands from a National DNA Repository of deaf individuals.

Results: Fifty-two of 318 heterozygous probands with pathogenic GJB2 sequence variants had a GJB6 deletion. Additionally, eight probands had an isolated heterozygous GJB6 deletion that did not explain their hearing loss. In two deaf subjects, including one proband, a homozygous GJB6 deletion was the cause for their hearing loss, a rare occurrence not reported to date.

Conclusion: This study represents the largest US cohort of deaf individuals harboring GJB2 and GJB6 variants, including unique subsets of families with deaf parents. Testing additional members to clarify the phase of GJB2/GJB6 variants in multiplex families was crucial in interpreting clinical significance of the variants in the proband. It highlights the importance of determining the phase of GJB2/GJB6 variants when interpreting molecular test results especially in multiplex families with assortative mating.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.1171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196463PMC
April 2020

Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel.

Genet Med 2019 11 4;21(11):2442-2452. Epub 2019 Jun 4.

Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.

Purpose: Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants.

Methods: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed.

Results: The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants.

Conclusion: Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0535-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235630PMC
November 2019

Cancer Risk in Klippel-Trenaunay Syndrome.

Lymphat Res Biol 2019 12 2;17(6):630-636. Epub 2019 May 2.

Special Interest Group, The American Society of Pediatric Hematology Oncology, Chicago, Illinois.

Klippel-Trenaunay syndrome (KTS) is an overgrowth syndrome defined by capillary/venous/lymphatic malformations (CVLM) with soft tissue and/or bone hypertrophy. Whether KTS predisposes to cancer is not clear. We surveyed members of the K-T Support Group (KTSG) and reviewed PubMed for "Klippel Trenaunay Syndrome" or "CVLM" and "cancer." Individuals with cancer were reviewed for confirmation of KTS, tumor type, location, and age at presentation. Of 223 KTSG respondents, 24 (10.8%) reported 26 malignancies or benign brain tumors (diagnosed from 6 months to 68 years of age, median 41 years), including 3 who were younger than 18 years (2 with Wilms tumor). Nine of twenty-six cancers were basal cell carcinomas (4% of respondents). From 475 articles, we identified 11 cancers or brain tumors in 10 individuals with KTS. Four of these were in children (Wilms tumor  = 2; rhabdomyosarcoma  = 1; serous borderline tumor  = 1). Tumors in adults included basal cell carcinoma ( = 1), squamous cell carcinoma of skin ( = 2), and angiosarcoma, Hodgkin disease, glioblastoma, malignant hemangiopericytoma in one patient each. Ulceration or lymphedema associated with VLM or capillary malformations were associated with some basal cell or squamous cell carcinomas and angiosarcomas. The risk of embryonal cancer other than Wilms tumor in children with KTS does not appear to be higher than in the general population. Wilms tumor incidence is under 5%, and routine surveillance is not indicated. In adults, particular attention should be paid to skin in the area of malformations. These conclusions may not apply to all overgrowth syndromes with vascular malformations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/lrb.2018.0049DOI Listing
December 2019

Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans.

Mol Genet Genomic Med 2019 06 23;7(6):e656. Epub 2019 Apr 23.

Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia.

Background: Craniosynostosis, or premature fusion of the skull sutures, is a group of disorders that can present in isolation (nonsyndromic) or be associated with other anomalies (syndromic). Delineation of syndromic craniosynostosis is confounded due to phenotypic overlap, variable expression as well as molecular heterogeneity. We report on an infant who presented at birth with multisuture synostosis, turribrachycephaly, midface hypoplasia, beaked nose, low set ears, a high palate and short squat appearing thumbs, and great toes without deviation. The additional MRI findings of choanal stenosis and a Chiari I malformation suggested a diagnosis of Pfeiffer syndrome. First tier molecular testing did not reveal a pathogenic variant.

Methods: Whole exome sequencing on DNA samples from the proband and her unaffected parents was utilized to delineate the variant causative for the Pfeiffer syndrome diagnosis.

Results: On whole exome sequencing, a de novo NM_000142.4:c.1428C>A missense variant causing a p.Ala391Glu amino acid change in FGFR3 has been identified. The p.Ala391Glu change has been predominantly identified in patients with Crouzon syndrome with acanthosis nigricans.

Conclusions: This finding illustrates the first reported case of a child with an overlap with Pfeiffer syndrome to have the p.Ala391Glu variant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565579PMC
June 2019

Analysis of risk factors associated with unilateral hearing loss in children who initially passed newborn hearing screening.

Int J Pediatr Otorhinolaryngol 2018 Mar 2;106:100-104. Epub 2018 Feb 2.

Department of Otolaryngology-HNS, Virginia Commonwealth University, 401 North 11th Street, PO Box 980146, Richmond, VA, 23298, United States.

Objective: To analyze 2007 Joint Committee on Infant Hearing (JCIH) risk factors in children with confirmed unilateral hearing loss (UHL) who initially passed newborn hearing screening.

Methods: Retrospective record review of 16,108 infants who passed newborn hearing screening but had one or more JCIH risk factors prompting subsequent follow-up through the universal newborn hearing screening (UNHS) program in Virginia from 2010 to 2012. The study was reviewed and qualified as exempt by the Virginia Commonwealth University Institutional Review Board (IRB) and the Virginia Department of Health.

Results: Over the 2-year study period, 14896 (4.9% of total births) children passed UNHS but had the presence of one or more JCIH risk factor. Ultimately, we identified 121 babies from this group with confirmed hearing loss (0.7%), with 48 babies (0.2%) showing UHL. The most common risk factors associated with the development of confirmed UHL after passing the initial screen were neonatal indicators, craniofacial anomalies, family history, and stigmata of syndrome associated with hearing loss.

Conclusion: Neonatal indicators and craniofacial anomalies were the categories most often found in children with confirmed unilateral hearing loss who initially passed their newborn hearing screen. While neonatal indicators were also the most common associated risk factor in all hearing loss, craniofacial abnormalities are relatively more common in children with UHL who initially passed newborn hearing screening. Further studies assessing the etiology underlying the hearing loss and risk factor associations are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijporl.2018.01.024DOI Listing
March 2018

Natural history and genotype-phenotype correlations in 72 individuals with SATB2-associated syndrome.

Am J Med Genet A 2018 04 13;176(4):925-935. Epub 2018 Feb 13.

Department of Pediatrics, The Barbara Bush Children's Hospital, Maine Medical Center, Portland, Maine.

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.38630DOI Listing
April 2018

Co-occurring Down syndrome and SUCLA2-related mitochondrial depletion syndrome.

Am J Med Genet A 2017 Oct 27;173(10):2720-2724. Epub 2017 Jul 27.

Department of Pediatrics, Division of Genetics and Metabolism, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Mitochondrial DNA depletion syndrome 5 (MIM 612073) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the beta subunit of the succinate-CoA ligase gene located within the 13q14 band. We describe two siblings of Hispanic descent with SUCLA2-related mitochondrial depletion syndrome (encephalomyopathic form with methylmalonic aciduria); the older sibling is additionally affected with trisomy 21. SUCLA2 sequencing identified homozygous p.Arg284Cys pathogenic variants in both patients. This mutation has previously been identified in four individuals of Italian and Caucasian descent. The older sibling with concomitant disease has a more severe phenotype than what is typically described in patients with either SUCLA2-related mitochondrial depletion syndrome or Down syndrome alone. The younger sibling, who has a normal female chromosome complement, is significantly less affected compared to her brother. While the clinical and molecular findings have been reported in about 50 patients affected with a deficiency of succinate-CoA ligase caused by pathogenic variants in SUCLA2, this report describes the first known individual affected with both a mitochondrial depletion syndrome and trisomy 21.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.38351DOI Listing
October 2017

Genetic hearing loss: the journey of discovery to destination - how close are we to therapy?

Authors:
Arti Pandya

Mol Genet Genomic Med 2016 Nov 21;4(6):583-587. Epub 2016 Nov 21.

Division of Genetics and Metabolism Department of Pediatrics University of North Carolina Chapel Hill North Carolina.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118202PMC
November 2016

American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss.

Genet Med 2014 Apr 20;16(4):347-55. Epub 2014 Mar 20.

Hearing loss is a common and complex condition that can occur at any age, can be inherited or acquired, and is associated with a remarkably wide array of etiologies. The diverse causes of hearing loss, combined with the highly variable and often overlapping presentations of different forms of hearing loss, challenge the ability of traditional clinical evaluations to arrive at an etiologic diagnosis for many deaf and hard-of-hearing individuals. However, identifying the etiology of a hearing loss may affect clinical management, improve prognostic accuracy, and refine genetic counseling and assessment of the likelihood of recurrence for relatives of deaf and hard-of-hearing individuals. Linguistic and cultural identities associated with being deaf or hard of hearing can complicate access to and the effectiveness of clinical care. These concerns can be minimized when genetic and other health-care services are provided in a linguistically and culturally sensitive manner. This guideline offers information about the frequency, causes, and presentations of hearing loss and suggests approaches to the clinical evaluation of deaf and hard-of-hearing individuals aimed at identifying an etiologic diagnosis and providing informative and effective patient education and genetic counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2014.2DOI Listing
April 2014

SLITRK6 mutations cause myopia and deafness in humans and mice.

J Clin Invest 2013 May 1;123(5):2094-102. Epub 2013 Apr 1.

John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.

Myopia is by far the most common human eye disorder that is known to have a clear, albeit poorly defined, heritable component. In this study, we describe an autosomal-recessive syndrome characterized by high myopia and sensorineural deafness. Our molecular investigation in 3 families led to the identification of 3 homozygous nonsense mutations (p.R181X, p.S297X, and p.Q414X) in SLIT and NTRK-like family, member 6 (SLITRK6), a leucine-rich repeat domain transmembrane protein. All 3 mutant SLITRK6 proteins displayed defective cell surface localization. High-resolution MRI of WT and Slitrk6-deficient mouse eyes revealed axial length increase in the mutant (the endophenotype of myopia). Additionally, mutant mice exhibited auditory function deficits that mirrored the human phenotype. Histological investigation of WT and Slitrk6-deficient mouse retinas in postnatal development indicated a delay in synaptogenesis in Slitrk6-deficient animals. Taken together, our results showed that SLITRK6 plays a crucial role in the development of normal hearing as well as vision in humans and in mice and that its disruption leads to a syndrome characterized by severe myopia and deafness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI65853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635725PMC
May 2013

The clinical and audiologic features of hearing loss due to mitochondrial mutations.

Otolaryngol Head Neck Surg 2013 Jun 22;148(6):1017-22. Epub 2013 Mar 22.

Virginia Commonwealth University Health Systems, Department of Otolaryngology-Head and Neck Surgery, 1200 East Broad St, West Hospital, Richmond, Virginia 23298-0146, USA.

Objectives: To characterize mitochondrial sequence variants present in a nationwide hereditary deafness DNA repository of samples from deaf subjects and to define the clinical presentation and audiometric characteristics of individuals with a mitochondrial sequence variant.

Study Design: Retrospective review of results for select mitochondrial mutations performed on DNA samples from subjects compiled from 1997 to 2009.

Setting: National hereditary deafness DNA repository.

Subjects And Methods: Available samples from subjects in the repository were screened to identify those with mitochondrial sequence variants. Clinical data on the nature of mutation, type and severity of the hearing loss, and sex, age at diagnosis, family history of hearing loss, and ethnicity were analyzed.

Results: Eighty-six patients were identified with mitochondrial mutations or 3.5% of the subjects studied. Among those with mitochondrial mutations, 21 (24.4%) had the m.7445A>G substitution, 18 (20.9%) had the m.1555A>G substitution, 18 (20.9%) had the m.961T>G substitution, and 29 (33.7%) had a m.961delT+C(n) complex deletion. The majority of patients had bilateral severe to profound hearing loss. Fifty-three (62%) patients were female, and a family history of hearing loss was documented in 66 (76.7%) patients. The deafness was recognized prior to 3 years of age in 26 patients.

Conclusion: Mitochondrial deafness in this sample was associated with a variety of genetic mutations and a wide spectrum of clinical presentations. Because of increased aminoglycoside susceptibility associated with some forms of mitochondrial deafness, matrilineal relatives may be at risk in those cases, highlighting the importance of making an accurate diagnosis prior to exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0194599813482705DOI Listing
June 2013

Risk factors associated with unilateral hearing loss.

JAMA Otolaryngol Head Neck Surg 2013 Jan;139(1):59-63

Departments of Otolaryngology–Head and Neck Surgery, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA.

Objective: To analyze the presence of Joint Committee on Infant Hearing (JCIH) risk factors and co-occurring birth defects (CBDs) in children with unilateral hearing loss (UHL).

Design: Retrospective review.

Setting: Statewide registry of universal newborn hearing screen data for all children born in Virginia from 2002 through 2008.

Patients: The study population comprised 371 children with confirmed UHL.

Main Outcome Measures: Universal newborn hearing screen status, presence or absence of JCIH risk factors, and CBDs

Results: Of the 371 children with confirmed unilateral hearing loss, 362 (97.5%) were identified through a failed universal newborn hearing screen. Of these 362 children, 252 (69.6%) had no JCIH risk factors and 110 (30.3%) had 1 or more risk factor reported. Nine children (2.5%) with 1 or more risk factors passed the universal newborn hearing screen but had later-onset UHL. Craniofacial anomaly was the most commonly reported JCIH risk factor in 48 children (43.6%). A family history of permanent childhood hearing loss was present in 24 children (21.8%). Twenty children (18.2%) had stigmata associated with a syndrome including hearing loss. Of the 110 children with UHL and a JCIH risk factor, additional CBDs were identified in 83 (75.5%). An ear-specific anomaly was most prevalent in 37 infants (44.6%), followed by cardiovascular anomalies in 34 infants (41.0%).

Conclusions: Thirty percent of children with confirmed UHL had a JCIH risk factor, most commonly craniofacial anomalies, family history of hearing loss, and stigmata of syndromes associated with hearing loss. However, the absence of JCIH risk factors does not preclude the development of UHL. Further studies assessing the etiology of UHL and risk factor associations are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoto.2013.1097DOI Listing
January 2013

GPSM2 mutations in Chudley-McCullough syndrome.

Am J Med Genet A 2012 Nov 14;158A(11):2972-3. Epub 2012 Sep 14.

Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.35636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657751PMC
November 2012

Performance evaluation of two methods using commercially available reagents for PCR-based detection of FMR1 mutation.

J Mol Diagn 2012 Sep 2;14(5):476-86. Epub 2012 Jul 2.

Division of Molecular Diagnostics, Department of Pathology, Molecular Diagnostics Laboratory, Virginia Commonwealth University, Richmond, Virginia 23298-0248, USA.

The current workflow for clinical Fragile X testing is time consuming and labor intensive. Recently developed PCR-based methods simplify workflow, amplify full mutation alleles, and improve sensitivity for detecting low-level mosaicism. We evaluated the performance characteristics and workflow of two methods using commercially available reagents for determining FMR1 mutation status. We also tested each method's ability to detect mosaicism (range, 100% to 1% for males; 50% to 1% for females). One method used reagents from Asuragen (AmplideX FMR1 PCR, research use only). The second method used analyte specific reagents from Abbott Molecular, including FMR1 Primer 1 (for repeat sizing) and FMR1 Primer 2 (for screening of expanded alleles). Each reaction was evaluated for accuracy, precision, correlation with previous results, and workflow. Both methods performed equally well in accuracy and precision studies using NIST standards and previously characterized Coriell samples. Both methods showed 100% concordance with results from a previous consensus study and for previously analyzed patient samples. The Asuragen reagents were able to detect full mutation mosaicism down to 5% and premutation mosaicism to 1%. The Abbott Molecular Primer 2 reagents were able to detect both full mutation and premutation mosaicism down to 25%. Both PCR-based methods for the determination of FMR1 mutation status performed well, with expected results in their final diagnoses, and differed significantly only in their workflow.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2012.03.005DOI Listing
September 2012

Etiology of unilateral hearing loss in a national hereditary deafness repository.

Am J Otolaryngol 2012 Sep-Oct;33(5):590-4. Epub 2012 Apr 24.

Department of Otolaryngology, Virginia Commonwealth University, Richmond, VA 23298, USA.

Purpose: The aim of this study was to characterize the genetic, audiologic, and epidemiologic characteristics of unilateral hearing loss (HL) in a national hereditary deafness repository.

Materials And Methods: This is a prospective clinical study involving 34 subjects identified in a national hereditary deafness repository. Clinical data and family history of HL were obtained on enrollment. Candidate deafness genes were screened by single-stranded conformation polymorphism, and mutations were confirmed with sequencing.

Results: Thirty-four subjects (19 males, 15 females) with unilateral HL were identified, ranging in age from 2 months to 36 years. The mean age at diagnosis was 7 years, and the left ear was affected in 62% of the cases. The racial distribution of our sample was 62% white, 23% African American, and 15% Hispanic. Imaging results were available in 47%, and most (69%) were considered normal. Nineteen percent had enlarged vestibular aqueducts, 2 had ipsilateral Mondini dysplasia, and 1 had a common cavity deformity. Twenty subjects (59%) had a family history of HL, with 26% specifically reporting familial unilateral HL. Mutational screening revealed sequence variants in the GJB2 (connexin 26), GJB3 (connexin 31), TECTA, and COCH genes. Two novel mutations were detected in COCH and TECTA.

Conclusions: Sequence variants in known deafness genes were detected in more than one-third of our study population, suggesting that gene/gene or gene/environmental interactions may indeed play a role in the etiology of some cases of unilateral deafness. Further prospective studies including congenital cytomegalovirus screening at birth and molecular screening of deafness genes in children with congenital unilateral HL will be required to establish the etiology of unilateral deafness with certainty.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjoto.2012.03.005DOI Listing
January 2013

Intraventricular twin fetuses in fetu.

J Neurosurg Pediatr 2012 Jan;9(1):17-23

Department of Pathology, Virginia Commonwealth University Health System, Richmond, Virginia 23298-0662, USA.

The authors report a rare case of multiple intracranial fetuses in fetu, fulfilling Willis' traditional criteria, which include an axial and appendicular skeleton with surrounding organized tissue. This case was ascertained from studies of a full-term female neonate who presented with ventriculomegaly. A CT scan showed intracranial calcifications that were suggestive of an axial skeleton. Her birth weight was 3.176 kg (50th-75th percentile), length was 52 cm (90th percentile), head circumference was 35 cm (50th-75th percentile), and Apgar scores were 7 and 8 at 1 and 5 minutes, respectively. Prenatal ultrasonography studies performed at 12 weeks and 5 days, and 19 weeks and 6 days revealed normal findings. A 37-week prenatal ultrasonography study showed ventriculomegaly and obstructive hydrocephalus, with a possible intracranial teratoma. Cranial imaging at birth with ultrasonography, CT and MR imaging, and MR angiography demonstrated 2 complex intraventricular masses with cystic, solid, and bony elements. A craniotomy with resection of the masses was performed at 3 months of age. The infant survived and is now 12 months old with some developmental progress. Two axial skeletons, with accompanying rib cage and extremities, including well-formed feet and toes, were noted. Both anencephalic structures had skin with hair, fat, skeletal and smooth muscle, and bony structures with bone marrow and focal areas of calcification. Multiple viscera were present and included thymus, bowel, stomach, salivary gland, kidney, adrenal gland, lung, and presumed adnexal structures. A diagnosis of fetuses in fetu was rendered. Chromosomal studies of the child and tissue from the 2 fetuses in fetu showed normal female karyotypes. A single nucleotide polymorphism array analysis from the proband infant and tissue from the 2 identified fetuses in fetu appeared to be genetically identical. These results are consistent with a monozygotic twin embryonic origin of the fetus in fetu tissue, which is a mechanism that has been suggested in previous reports in which karyotypes, blood types, and limited genetic loci have been studied. This is the first report of a rare example of intracranial intraventricular twin fetuses in fetu for which a genome-wide single nucleotide polymorphism assay has confirmed their genetic identity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3171/2011.10.PEDS11196DOI Listing
January 2012

Impact of co-occurring birth defects on the timing of newborn hearing screening and diagnosis.

Am J Audiol 2011 Dec 22;20(2):132-9. Epub 2011 Sep 22.

Virginia Commonwealth University, Richmond, USA.

Purpose: Early detection of hearing loss in all newborns and timely intervention are critical to children's cognitive, verbal, behavioral, and social development. The initiation of appropriate early intervention services before 6 months of age can prevent or reduce negative developmental consequences. The purpose of this study was to assess, using large, population-based registries, the effect of co-occurring birth defects (CBDs) on the timing and overall rate of hearing screening and diagnosis.

Method: The authors linked statewide data from newborn hearing screenings, a birth defects registry, and birth certificates to assess the timeliness of newborn hearing screening and diagnosis of hearing loss (HL) for infants with and without CBDs in 485 children with confirmed HL.

Results: Nearly one third (31.5%) of children with HL had 1 or more CBDs. The presence of CBDs prolonged the time of the initial infant hearing screening, which contributed to further delays in the subsequent diagnosis of HL.

Conclusions: Better coordination of HL assessment into treatment plans for children with CBDs may enable earlier diagnosis of HL and provide opportunities for intervention that will affect long-term developmental outcomes for these children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1044/1059-0889(2011/10-0049)DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877695PMC
December 2011

Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment.

Am J Med Genet A 2011 Jun 28;155A(6):1298-313. Epub 2011 Apr 28.

Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Denmark.

Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.33970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100366PMC
June 2011

Vestibular dysfunction in DFNB1 deafness.

Am J Med Genet A 2011 May 4;155A(5):993-1000. Epub 2011 Apr 4.

Department of Otolaryngology, Virginia Commonwealth University, Richmond, USA.

Mutations of GJB2 and GJB6 (connexin-26 and 30) at the DFNB1 locus are the most common cause of autosomal recessive, nonsyndromic deafness. Despite their widespread expression throughout the vestibular system, vestibular dysfunction has not been widely recognized as a commonly associated clinical feature. The observations of vertigo accompanying DFNB1 deafness in several large families prompted our hypothesis that vestibular dysfunction may be an integral, but often overlooked, component of DFNB1 deafness. Our aim was to define the prevalence of vestibular dysfunction in Cases of DFNB1 deafness and Controls with other forms of deafness. We developed and used a survey to assess symptoms of vestibular dysfunction, medical, and family history was distributed to Cases with deafness due to pathogenic GJB2 and/or GJB6 mutations and deaf Controls without DFNB1 deafness. Our results showed: Surveys were returned by 235/515 Cases (46%) with DFNB1 mutations and 121/321 Controls (38%) without these mutations. The mean age of Cases (41) was younger than Controls (51; P < 0.001). Vestibular dysfunction was reported by 127 (54%) of Cases and was present at significantly higher rates in Cases than in deaf Controls without DFNB1 deafness (P < 0.03). Most (63%) had to lie down in order for vertigo to subside, and 48% reported that vertigo interfered with activities of daily living. Vertigo was reported by significantly more Cases with truncating than non-truncating mutations and was also associated with a family history of dizziness. We conclude that vestibular dysfunction appears to be more common in DFNB1 deafness than previously recognized and affects activities of daily living in many patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.33828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080433PMC
May 2011

Presence of SPINK-1 variant alters the course of chronic pancreatitis.

J Gastroenterol Hepatol 2011 Jun;26(6):965-9

Department of Gastroenterology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23233, USA.

Background And Aims: There is growing evidence that genetic mutations/variants increase susceptibility to the development and progression of chronic pancreatitis (CP). Several mutations have been identified that have a direct and indirect role in events leading to CP. Mutations in the serine protease inhibitor, Kazal type-1 (SPINK-1) gene have been reported to lower the threshold for pancreatitis in the presence of other genetic or environmental factors. The prevalence and impact of SPINK-1 mutations on the clinical course and outcomes of CP remains unclear. This study was conducted to assess the prevalence of the SPINK-1/N34S variant in patients with CP, and to understand the impact of the SPINK-1 mutation on the natural history of CP.

Methods: A retrospective-prospective analysis of 239 patients with CP was performed. A detailed history, including duration of symptoms, type of pain (intermittent flares or chronic continuous pain), number of flares requiring hospital admission, alcohol and smoking history, and family history was obtained. The baseline morphological stage of CP was categorized by Cambridge classification. Clinical outcome variables included frequency and severity of pain episodes, presence of exocrine failure (defined by presence of steatorrhea and/or fecal elastase < 200 ug/g), and diabetes. The genetic tests included the cationic trypsinogen gene-1 mutation, cystic fibrosis gene mutations (Genzyme assay), and the SPINK-1/N34S mutation.

Results: Of the 239 patients with CP, 13 (5.4%) were positive for the SPINK-1/N34S mutation. There were 35 (14.6%) patients with idiopathic pancreatitis (IP) in this cohort. Most of the patients who were positive for the SPINK-1/N34S mutation had IP and were Caucasian (69.2%). The patients with the SPINK-1/N34S mutation had a younger age of onset (32.9 ± 10.2 vs 40.1 ± 13.6 years; P = 0.108) than those with IP and no mutation. Over a median follow up of 9.6 years, the patients with the SPINK-1/N34S mutation had a significantly greater number of acute flares each year, as compared to those without the mutation (11.8 ± 1.5 vs 4 ± 0.98; P = 0.0001).

Conclusions: The prevalence of the SPINK-1/N34S mutation in patients with CP is 5.4%, and is approximately 37.1% in patients with IP. These mutations are more prevalent in Caucasian patients with CP. The SPINK-1/N34S mutation predisposes to early onset IP and more frequent acute flares of pancreatitis that might ultimately lead to pancreatic insufficiency. The patients with IP and borderline alcohol history should be considered for testing for genetic analysis, including SPINK-1 mutations, initially restricted to clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1440-1746.2011.06713.xDOI Listing
June 2011

GJB2 mutations in Mongolia: complex alleles, low frequency, and reduced fitness of the deaf.

Ann Hum Genet 2010 Mar 27;74(2):155-64. Epub 2010 Jan 27.

The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Leonard M. Miller School of Medicine, Miami, Florida 33136, USA.

We screened the GJB2 gene for mutations in 534 (108 multiplex and 426 simplex) probands with non-syndromic sensorineural deafness, who were ascertained through the only residential school for the deaf in Mongolia, and in 217 hearing controls. Twenty different alleles, including four novel changes, were identified. Biallelic GJB2 mutations were found in 4.5% of the deaf probands (8.3% in multiplex, 3.5% in simplex). The most common mutations were c.IVS1 + 1G > A (c.-3201G > A) and c.235delC with allele frequencies of 3.5% and 1.5%, respectively. The c.IVS1 + 1G > A mutation appears to have diverse origins based on associated multiple haplotypes. The p.V27I and p.E114G variants were frequently detected in both deaf probands and hearing controls. The p.E114G variant was always in cis with the p.V27I variant. Although in vitro experiments using Xenopus oocytes have suggested that p.[V27I;E114G] disturbs the gap junction function of Cx26, the equal distribution of this complex allele in both deaf probands and hearing controls makes it a less likely cause of profound congenital deafness. We found a lower frequency of assortative mating (37.5%) and decreased genetic fitness (62%) of the deaf in Mongolia as compared to the western populations, which provides an explanation for lower frequency of GJB2 deafness in Mongolia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1469-1809.2010.00564.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739516PMC
March 2010

Fitness among individuals with early childhood deafness: Studies in alumni families from Gallaudet University.

Ann Hum Genet 2010 Jan 20;74(1):27-33. Epub 2009 Nov 20.

Hussman Institute for Human Genomics, University of Miami, FL 33136, USA.

The genetic fitness of an individual is influenced by their phenotype, genotype and family and social structure of the population in which they live. It is likely that the fitness of deaf individuals was quite low in the Western European population during the Middle Ages. The establishment of residential schools for deaf individuals nearly 400 years ago resulted in relaxed genetic selection against deaf individuals which contributed to the improved fitness of deaf individuals in recent times. As part of a study of deaf probands from Gallaudet University, we collected pedigree data, including the mating type and the number and hearing status of the children of 686 deaf adults and 602 of their hearing siblings. Most of these individuals had an onset of severe to profound hearing loss by early childhood. Marital rates of deaf adults were similar to their hearing siblings (0.83 vs. 0.85). Among married individuals, the fertility of deaf individuals is lower than their hearing siblings (2.06 vs. 2.26, p = 0.005). The fitness of deaf individuals was reduced (p = 0.002). Analysis of fertility rates after stratification by mating type reveals that matings between two deaf individuals produced more children (2.11) than matings of a deaf and hearing individual (1.85), suggesting that fertility among deaf individuals is influenced by multiple factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1469-1809.2009.00553.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804774PMC
January 2010

Provision of genetic services for hearing loss: results from a national survey and comparison to insights obtained from previous focus group discussions.

J Genet Couns 2009 Dec 2;18(6):618-21. Epub 2009 Oct 2.

Department of Human and Molecular Genetics, Virginia Commonwealth University, P.O. Box 980033, Richmond, VA 23298-0033, USA.

Hearing loss is a common sensory deficit and more than 50% of affected individuals have a genetic etiology. The discovery of 40 genes and more than 100 loci involved in hearing loss has made genetic testing for some of these genes widely available. Genetic services for deafness are also being sought more often due to the early identification of hearing loss through newborn screening services. The motivations for pursuing genetic testing, and how genetic services are provided to the client may differ among individuals. Additionally, information obtained through genetic testing can be perceived and used in different ways by parents of deaf children and deaf adults. This study aimed to follow up on focus group studies published earlier with a quantitative survey instrument and assess the preference of consumers for provision of genetic services. We conducted a national survey of hearing and deaf parents of children with hearing loss and of deaf adults. Data was compared and analyzed by hearing status of the participant, their community affiliation and the genetic testing status using nominal logistic regression. Consistent with our focus group results, the survey participants thought that a genetic counselor/geneticist would be the most appropriate professional to provide genetics services. Statistically significant differences were noted in the preferred choice of provider based on the genetic testing status. Parents preferred that genetic evaluation, including testing, occur either immediately at or a few months after the audiologic diagnosis of hearing loss. This data should help providers in clinical genetics keep patient preferences at the helm and provide culturally competent services.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10897-009-9246-8DOI Listing
December 2009

Impact of genetic advances and testing for hearing loss: results from a national consumer survey.

Am J Med Genet A 2009 Jun;149A(6):1159-68

Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298-0033, USA.

Hearing loss is a common neuro-sensory deficit; nearly 50% of children with hearing loss have a genetic etiology. With the discovery of 40 genes and more than 100 loci involved in hearing loss, genetic testing is becoming more widely available. The information obtained through genetic testing can be perceived and used in different ways by parents of deaf children and deaf adults, based on their prior knowledge and understanding of these advances. It is therefore important to clarify the feelings of these potential consumers towards genetic services for hearing loss and understand their goals for genetic testing. The present study evaluates the feelings of consumers towards the advances in the genetics of hearing loss, the motivations for pursuing testing, and the perceived impact testing may have on their lives. We surveyed 808 parents of children with hearing loss nationally and 156 young deaf adults at Gallaudet University. In this study, learning the etiology of the hearing loss was the most commonly cited motivation for pursuing genetic testing and for parents was the most commonly cited outcome that genetic testing may have on their children's lives. Culturally Deaf respondents were less likely to believe that genetic testing will impact their lives or their children's lives and were less likely to report positive feelings about advances in the genetics of hearing loss. Cultural affiliation and genetic testing status, rather than hearing status, contributed more to the participants' responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.32800DOI Listing
June 2009

Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene.

Eur J Hum Genet 2009 Apr 5;17(4):517-24. Epub 2008 Nov 5.

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.

Hereditary hearing loss (HL) is a very heterogeneous trait, with 46 gene identifications for non-syndromic HL. Mutations in GJB2 cause up to half of all cases of severe-to-profound congenital autosomal recessive non-syndromic HL, with 35delG being the most frequent mutation in Caucasians. Although a genotype-phenotype correlation has been established for most GJB2 genotypes, the HL of 35delG homozygous patients is mild to profound. We hypothesise that this phenotypic variability is at least partly caused by the influence of modifier genes. By performing a whole-genome association (WGA) study on 35delG homozygotes, we sought to identify modifier genes. The association study was performed by comparing the genotypes of mild/moderate cases and profound cases. The first analysis included a pooling-based WGA study of a first set of 255 samples by using both the Illumina 550K and Affymetrix 500K chips. This analysis resulted in a ranking of all analysed single-nucleotide polymorphisms (SNPs) according to their P-values. The top 250 most significantly associated SNPs were genotyped individually in the same sample set. All 192 SNPs that still had significant P-values were genotyped in a second independent set of 297 samples for replication. The significant P-values were replicated in nine SNPs, with combined P-values between 3 x 10(-3) and 1 x 10(-4). This study suggests that the phenotypic variability in 35delG homozygous patients cannot be explained by the effect of one major modifier gene. Significantly associated SNPs may reflect a small modifying effect on the phenotype. Increasing the power of the study will be of greatest importance to confirm these results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2008.201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2883287PMC
April 2009

A comparative analysis of the genetic epidemiology of deafness in the United States in two sets of pedigrees collected more than a century apart.

Am J Hum Genet 2008 Aug 24;83(2):200-7. Epub 2008 Jul 24.

Department of Biology, Gallaudet University, Washington, DC 20002, USA.

In 1898, E.A. Fay published an analysis of nearly 5000 marriages among deaf individuals in America collected during the 19(th) century. Each pedigree included three-generation data on marriage partners that included at least one deaf proband, who were ascertained by complete selection. We recently proposed that the intense phenotypic assortative mating among the deaf might have greatly accelerated the normally slow response to relaxed genetic selection against deafness that began in many Western countries with the introduction of sign language and the establishment of residential schools. Simulation studies suggest that this mechanism might have doubled the frequency of the commonest forms of recessive deafness (DFNB1) in this country during the past 200 years. To test this prediction, we collected pedigree data on 311 contemporary marriages among deaf individuals that were comparable to those collected by Fay. Segregation analysis of the resulting data revealed that the estimated proportion of noncomplementary matings that can produce only deaf children has increased by a factor of more than five in the past 100 years. Additional analysis within our sample of contemporary pedigrees showed that there was a statistically significant linear increase in the prevalence of pathologic GJB2 mutations when the data on 441 probands were partitioned into three 20-year birth cohorts (1920 through 1980). These data are consistent with the increase in the frequency of DFNB1 predicted by our previous simulation studies and provide convincing evidence for the important influence that assortative mating can have on the frequency of common genes for deafness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2008.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2495057PMC
August 2008
-->