检索结果-内蒙古大学图书馆

Optical genome mapping unveils hidden structural variants in neurodevelopmental disorders

SCIENTIFIC REPORTS 2024年第1期14卷 1-7页

作者： schrauwen, isabelle Rajendran, Yasmin Acharya, Anushree Ohman, Susanna Arvio, Maria Paetau, Ritva Siren, Auli Avela, Kristiina Granvik, Johanna Leal, Suzanne M. Maatta, Tuomo Kokkonen, Hannaleena Jarvela, Irma Columbia Univ Gertrude H Sergievsky Ctr Dept Neurol Ctr Stat GenetMed Ctr 630 W 168Th St New York NY 10032 USA Karkulla Samkommun Kirjala Finland Paijat Hame Wellbeing Serv Neurol Lahti Finland Univ Helsinki Dept Child Neurol Helsinki Finland Helsinki Univ Hosp Helsinki Finland Kanta Hame Cent Hosp Hameenlinna Finland Univ Turku Inst Biomed Turku Finland Wellbeing Serv Cty Ostrobothnia Kokkola Finland Columbia Univ Taub Inst Alzheimers Dis & Aging Brain Med Ctr New York NY USA Wellbeing Serv Cty Kainuu Kajaani Finland Oulu Univ Hosp Northern Finland Lab Ctr NordLab Oulu Finland Oulu Univ Hosp Med Res Ctr Oulu Finland Univ Oulu Oulu Finland Univ Helsinki Dept Med Genet Helsinki Finland

While short-read sequencing currently dominates genetic research and diagnostics, it frequently falls short of capturing certain structural variants (SVs), which are often implicated in the etiology of neurodevelopmental disorders (NDDs). Optical genome mapping (OGM) is an innovative technique capable of capturing SVs that are undetectable or challenging-to-detect via short-read methods. This study aimed to investigate NDDs using OGM, specifically focusing on cases that remained unsolved after standard exome sequencing. OGM was performed in 47 families using ultra-high molecular weight DNA. Single-molecule maps were assembled de novo, followed by SV and copy number variant calling. We identified 7 variants of interest, of which 5 (10.6%) were classified as likely pathogenic or pathogenic, located in BCL11A, OPHN1, PHF8, SON, and NFIA. We also identified an inversion disrupting NAALADL2, a gene which previously was found to harbor complex rearrangements in two NDD cases. Variants in known NDD genes or candidate variants of interest missed by exome sequencing mainly consisted of larger insertions (>1kbp), inversions, and deletions/duplications of a low number of exons (1-4 exons). In conclusion, in addition to improving molecular diagnosis in NDDs, this technique may also reveal novel NDD genes which may harbor complex SVs often missed by standard sequencing techniques.

关键词： Optical genome mapping Neurodevelopmental disorders Structural variants Copy number variants Unsolved cases

来源：评论

学校读者我要写书评

暂无评论

Heterogeneous genetic patterns in bilateral perisylvian polymicrogyria: insights from a Finnish family cohort

BRAIN COMMUNICATIONS

引用

BRAIN COMMUNICATIONS 2024年第3期6卷 fcae142页

作者： Jarvela, Irma Paetau, Ritva Rajendran, Yasmin Acharya, Anushree Bharadwaj, Thashi Leal, Suzanne M. Lehesjoki, Anna-Elina Palomaki, Maarit schrauwen, isabelle Univ Helsinki Dept Med Genet POB 720 Helsinki 00251 Finland Univ Helsinki Dept Child Neurol Helsinki 00290 Finland Helsinki Univ Hosp Helsinki 00290 Finland Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Dept NeurolMed Ctr 630 W 168th St New York NY 10032 USA Columbia Univ Med Ctr Taub Inst New York NY 10032 USA Folkhalsan Res Ctr Helsinki 00290 Finland Univ Helsinki Med Imaging Ctr Helsinki 00290 Finland

Bilateral perisylvian polymicrogyria is the most common form of regional polymicrogyria within malformations of cortical development, constituting 20% of all malformations of cortical development. Bilateral perisylvian polymicrogyria is characterized by an excessive folding of the cerebral cortex and abnormal cortical layering. Notable clinical features include upper motoneuron dysfunction, dysarthria and asymmetric quadriparesis. Cognitive impairment and epilepsy are frequently observed. To identify genetic variants underlying bilateral perisylvian polymicrogyria in Finland, we examined 21 families using standard exome sequencing, complemented by optical genome mapping and/or deep exome sequencing. Pathogenic or likely pathogenic variants were identified in 5/21 (24%) of families, of which all were confirmed as de novo. These variants were identified in five genes, i.e. DDX23, NUS1, SCN3A, TUBA1A and TUBB2B, with NUS1 and DDX23 being associated with bilateral perisylvian polymicrogyria for the first time. In conclusion, our results confirm the previously reported genetic heterogeneity of bilateral perisylvian polymicrogyria and underscore the necessity of more advanced methods to elucidate the genetic background of bilateral perisylvian polymicrogyria. J & auml;rvel & auml;et al. report de novo pathogenic or likely pathogenic variants in five genes underlying bilateral perisylvian polymicrogyria in a Finnish cohort using exome sequencing, optical genome mapping and deep sequencing. The outcome identified variants in 24% of families, expanding the genetic heterogeneity of bilateral perisylvian polymicrogyria. Graphical Abstract

关键词： biparietal perisylvian polymicrogyria exome sequencing gene de novo optical genome mapping

来源：评论

学校读者我要写书评

暂无评论

Whole-exome sequencing reveals known and candidate genes for hearing impairment in Mali

引用

HUMAN GENETICS AND GENOMICS ADVANCES 2025年第1期6卷 100391-100391页

作者： Yalcouye, Abdoulaye schrauwen, isabelle Traore, Oumou Bamba, Salia Aboagye, Elvis Twumasi Acharya, Anushree Bharadwaj, Thashi Latanich, Rachel Esoh, Kevin Fortes-Lima, Cesar A. de Kock, Carmen Jonas, Mario Maiga, Alassane dit Baneye Cisse, Cheick A. K. Sangare, Moussa A. Guinto, Cheick O. Landoure, Guida Leal, Suzanne M. Wonkam, Ambroise USTTB Fac Med & Odontostomatol Bamako Mali Univ Cape Town Fac Hlth Sci Dept Med Div Human Genet Cape Town South Africa Johns Hopkins Univ McKusick Nathans Inst Sch Med Baltimore MD 21218 USA Johns Hopkins Univ Sch Med Dept Genet Med Baltimore MD 21218 USA Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Med Ctr New York NY USA Columbia Univ Dept Neurol Med Ctr New York NY USA Ctr Hospitalier Univ Point G Serv Neurol Bamako Mali

Hearing impairment (HI) is the most common neurosensory disorder globally and is reported to be more prevalent in low-income countries. In high-income countries, up to 50% of congenital childhood HI is of genetic origin. However, there are limited genetic data on HI from sub-Saharan African populations. In this study, we investigated the genetic causes of HI in the Malian populations, using wholeexome sequencing. Furthermore, cDNA was transfected into HEK293T cells for localization and expression analysis in a candidate gene. Twenty-four multiplex families were enrolled, 50% (12/24) of which are consanguineous. Clustering methods showed patterns of admixture from non-African sources in some Malian populations. Variants were found in six known nonsyndromic HI (NSHI) genes, four genes that can underlie either syndromic HI (SHI) or NSHI, one SHI gene, and one novel candidate HI gene. Overall, 75% of families (18/24) were solved, and 94.4% (17/18) had variants in known HI genes including MYO15A, CDH23, MYO7A, GJB2, SLC26A4, PJVK, OTOGL, TMC1, CIB2, GAS2, PDCH15, and EYA1. A digenic inheritance ( CDH23 and PDCH15) was found in one family. Most variants (59.1%, 13/22) in known HI genes were not previously reported or associated with HI. The UBFD1 candidate HI gene, which was identified in one consanguineous family, is expressed in human inner ear organoids. Cell-based experiments in HEK293T showed that mutants UBFD1 had a lower expression, compared to wild type. We report the profile of known genes and the UBFD1 candidate gene for HI in Mali and emphasize the potential of gene discovery in African populations.

关键词： hearing impairment UBFD1 candidate gene admixture mapping Mali Africa

来源：评论

学校读者我要写书评

暂无评论

A novel 4.25 kb heterozygous deletion in PAX6 in a Chinese Han family with congenital aniridia combined with cataract and nystagmus

引用

BMC OPHTHALMOLOGY 2021年第1期21卷 353-353页

作者： Qian, Tianwei Chen, Chong Li, Caihua Gong, Qiaoyun Liu, Kun Wang, Gao schrauwen, isabelle Xu, Xun Shanghai Jiao Tong Univ Shanghai Gen Hosp Dept Ophthalmol 100 Haining Rd Shanghai 200080 Peoples R China Natl Clin Res Ctr Eye Dis Shanghai Peoples R China Shanghai Key Lab Ocular Fundus Dis Shanghai Peoples R China Shanghai Engn Ctr Visual Sci & Photomed Shanghai Peoples R China Shanghai Engn Ctr Precise Diag & Treatment Eye Di Shanghai Peoples R China Columbia Univ Med Ctr Dept Neurol 630W 168th St New York NY 10032 USA Singapore Natl Eye Ctr Singapore Eye Res Inst Singapore Singapore Genesky Biotechnol Inc Shanghai Peoples R China

Background The aim of this study is to identify the genetic defect in a Chinese family with congenital aniridia combined with cataract and nystagmus. Methods Complete ophthalmic examinations, including slit-lamp biomicroscopy, dilated indirect ophthalmoscopy, anterior segment photography, and anterior segment optical coherence tomography (OCT) were performed. Blood samples were collected from all family members and genomic DNA was extracted. Genome sequencing was performed in all family members and Sanger sequencing was used to verify variant breakpoints. Results All the thirteen members in this Chinese family, including seven patients and six normal people, were recruited in this study. The ophthalmic examination of affected patients in this family was consistent with congenital aniridia combined with cataract and nystagmus. A novel heterozygous deletion (NC_000011.10:g.31802307_31806556del) containing the 5 ' region of PAX6 gene was detected that segregated with the disease. Conclusion We detected a novel deletion in PAX6 responsible for congenital aniridia in the affected individuals of this Chinese family. The novel 4.25 kb deletion in PAX6 gene of our study would further broaden the genetic defects of PAX6 associated with congenital aniridia.

关键词： Congenital aniridia PAX6 Deletion Copy number variant

来源：评论

学校读者我要写书评

暂无评论

ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time

引用

GENETICS IN MEDICINE 2025年第5期27卷 101392页

作者： Tshering, Kezang C. DiStefano, Marina T. Oza, Andrea M. Ajuyah, Pamela Webb, Ryan Edoh, Enyonam Broeren, Ellie Ratliff, Julie Gitau, Vanessa Paris, Kelley Aburyyan, Amal Alexander, John Albano, Victoria Bai, Donglin Booth, Kevin T. A. Buonfiglio, Paula I. Charfeddine, Cherine Dalamon, Viviana del Castillo, Ignacio Moreno-Pelayo, Miguel Angel Duzkale, Hatice Dorshorst, Ben Faridi, Rabia Kenna, Margaret Lewis, Morag A. Luo, Minjie Lu, Yu Mkaouar, Rahma Matsunaga, Tatsuo Nara, Kiyomitsu Pandya, Arti Redfield, Shelby Roux, isabelle Schimmenti, Lisa A. schrauwen, isabelle Shaaban, Sherin Shen, Jun Vona, Barbara Smith, Richard J. Rehm, Heidi L. Azaiez, Hela Abou Tayoun, Ahmad N. Amr, Sami S. Broad Inst MIT & Harvard Cambridge MA USA Mass Gen Brigham Personalized Med Lab Mol Med 65 Landsdowne St Cambridge MA 02139 USA Univ Washington Dept Med Seattle WA USA Myriad Womens Hlth San Francisco CA USA Boston Childrens Hosp Dept Otolaryngol & Commun Enhancement Boston MA USA Western Univ Schulich Sch Med & Dent Dept Physiol & Pharmacol London ON Canada Indiana Univ Sch Med Dept Med & Mol Genet Indianapolis IN USA Indiana Univ Sch Med Dept Otolaryngol Head & Neck Surg Indianapolis IN USA Consejo Nacl Invest Cient & Tecn CONICET Inst Invest Ingn Genet & Biol Mol Dr Hector N Torr Lab Fisiol & Genet Aud Buenos Aires Argentina Univ Tunis El Manar Inst Pasteur Tunis Lab Biomed Genom & Oncogenet Tunis Tunisia Univ Manouba Inst Biotechnol Sidi Thabet Ariana Tunisia Hosp Univ Ramon y Cajal IRYCIS Serv Genet Madrid Spain Inst Salud Carlos III CB06 07 0048 CIBERER ISCIII Ctr Invest Biomed Red Enfermedades Raras Madrid Spain Color Hlth Burlingame CA USA Prevent Genet Marshfield WI USA Natl Inst Deafness & Other Commun Disorders NIH Lab Mol Genet Bethesda MD 20892 USA Kings Coll London Wolfson Sensory Pain & Regenerat Ctr London England Childrens Hosp Philadelphia Div Genom Diagnost Philadelphia PA 19104 USA Univ Penn Perelman Sch Med Dept Pathol & Lab Med Philadelphia PA USA Sichuan Univ West China Hosp Inst Rare Dis Chengdu Peoples R China Natl Hosp Org Tokyo Med Ctr Div Hearing & Balance Res Tokyo Japan UNC Sch Med Dept Pediat Div Genet & Metab Chapel Hill NC USA Mayo Clin Enterprise Dept Clin Genom Rochester MN USA Univ Arizona Coll Med Phoenix Dept Translat Neurosci Phoenix AZ 85721 USA Univ Utah Sch Med Dept Pathol Salt Lake City UT USA ARUP Labs Salt Lake City UT USA Harvard Med Sch Brigham & Womens Hosp Dept Pathol Boston MA USA Univ Med Ctr Gottingen Inst Human Genet Gottingen Germany Univ Med Ctr Gottingen Inst Auditory Neurosci Gottingen Germany Univ Med Ctr Gottingen InnerEarLab Gottingen Germany Univ Iowa De

Purpose: The Clinical Genome Resource (ClinGen) Hearing Loss Gene Curation Expert Panel was assembled in 2016 and has since curated 174 gene-disease relationships (GDRs) using ClinGen's semiquantitative framework. ClinGen mandates the timely recuration of all GDRs classified as Disputed, Limited, Moderate, and Strong every 2 to 3 years. Methods: Thirty-five GDRs met the criteria for recuration within 2 years of original curation. Previous evidence was reevaluated using the latest curation guidelines, and a comprehensive literature review was performed to obtain new evidence. Recurations were approved by the Gene Curation Expert Panel and published on the ClinGen website (***). Results: Eight of 35 GDRs (22%) changed their classification. Two Moderate and 5 Strong GDRs were upgraded to Definitive because of new case evidence. One Strong was subsumed under another Definitive GDR after evaluation of the lumping/splitting of disease entities. Twenty-seven of 35 patients remained unchanged, with little to no new evidence reported. Conclusion: Genes classified as Moderate and Strong were likely to build evidence and change their classification over time, whereas Limited were unlikely to gain evidence. These findings highlight the critical role of recuration in ensuring that genetic tests and research studies incorporate the most recent evidence into their efforts. (c) 2025 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： ClinGen Deafness Gene curation Genetic diagnosis Hearing loss

来源：评论

学校读者我要写书评

暂无评论

Autosomal recessive nonsyndromic hearing impairment in two Finnish families due to the population enriched CABP2 c.637+1G>T variant

引用

MOLECULAR GENETICS & GENOMIC MEDICINE 2022年第3期10卷 e1866页

作者： Bharadwaj, Thashi schrauwen, isabelle Acharya, Anushree Nouel-Saied, Liz M. Vaisanen, Marja-Leena Kraatari, Minna Rahikkala, Elisa Jarvela, Irma Kotimaki, Jouko Leal, Suzanne M. Columbia Univ Med Ctr Ctr Stat Genet Gertrude H Sergievsky Ctr New York NY 10032 USA Columbia Univ Med Ctr Dept Neurol New York NY 10032 USA Oulu Univ Hosp Northern Finland Lab Ctr NordLab Oulu Finland Oulu Univ Hosp Med Res Ctr Oulu Finland Univ Oulu Oulu Finland Oulu Univ Hosp PEDEGO Res Unit Dept Clin Genet Oulu Finland Oulu Univ Hosp Med Res Ctr Oulu Oulu Finland Univ Turku Inst Biomed Turku Finland Univ Helsinki Dept Med Genet Helsinki Finland Kainuu Cent Hosp Dept Otorhinolaryngol Kajaani Finland Columbia Univ Taub Inst Alzheimers Dis & Aging Brain Med Ctr New York NY 10032 USA

Background: The genetic architecture of hearing impairment in Finland is largely unknown. Here, we investigated two Finnish families with autosomal recessive nonsyndromic symmetrical moderate-to-severe hearing impairment. Methods: Exome and custom capture next-generation sequencing were used to detect the underlying cause of hearing impairment. Results: In both Finnish families, we identified a homozygous pathogenic splice site variant c.637+1G>T in CAPB2 that is known to cause autosomal recessive nonsyndromic hearing impairment. Four CABP2 variants have been reported to underlie autosomal recessive nonsyndromic hearing impairment in eight families from Iran, Turkey, Pakistan, Italy, and Denmark. Of these variants, the pathogenic splice site variant c.637+1G>T is the most prevalent. The c.637+1G>T variant is enriched in the Finnish population, which has undergone multiple bottlenecks that can lead to the higher frequency of certain variants including those involved in disease. Conclusion: We report two Finnish families with hearing impairment due to the CABP2 splice site variant c.637+1G>T.

关键词： autosomal recessive CABP2 hearing impairment

来源：评论

学校读者我要写书评

暂无评论

Further evidence of involvement of TMEM132E in autosomal recessive nonsyndromic hearing impairment

引用

JOURNAL OF HUMAN GENETICS 2020年第2期65卷 187-192页

作者： Liaqat, Khurram Hussain, Shabir Bilal, Muhammad Nasir, Abdul Acharya, Anushree Ali, Raja Hussain Nawaz, Shoaib Umair, Muhammad schrauwen, isabelle Ahmad, Wasim Leal, Suzanne M. Quaid I Azam Univ Fac Biol Sci Dept Biotechnol Islamabad Pakistan Baylor Coll Med Ctr Stat Genet Dept Mol & Human Genet Houston TX 77030 USA Quaid I Azam Univ Fac Biol Sci Dept Biochem Islamabad Pakistan Ajou Univ Dept Mol Sci & Technol Suwon 443749 South Korea Columbia Univ Ctr Stat Genet Gertrude H Sergievsky CtrMed Ctr Dept NeurolTaub Inst Alzheimers Dis & Aging Brai 630 W 168th St New York NY 10032 USA Boston Childrens Hosp Div Hematol Oncol Boston MA 02115 USA King Saud Bin Abdulaziz Univ Hlth Sci KAIMRC Med Genom Res Dept MNGHA POB 3660 Riyadh 11481 Saudi Arabia

Autosomal-recessive (AR) nonsyndromic hearing impairment (NSHI) displays a high degree of genetic heterogeneity with >100 genes identified. Recently, TMEM132E, which is highly expressed in inner hair cells, was suggested as a novel ARNSHI gene for DFNB99. A missense variant c.1259G>A: p.(Arg420Gln) in TMEM132E was identified that segregated with ARNSHI in a single Chinese family with two affected members. In the present study, a family of Pakistani origin with prelingual profound sensorineural hearing impairment displaying AR mode of inheritance was investigated via exome and Sanger sequencing. Compound heterozygous variants c.382G>T: p.(Ala128Ser) and c.2204C>T: p.(Pro735Leu) in TMEM132E were observed in affected but not in unaffected family members. TMEM132E variants identified in this and the previously reported ARNSHI family are located in the extracellular domain. In conclusion, we present a second ARNSHI family with TMEM132E variants which strengthens the evidence of the involvement of this gene in the etiology of ARNSHI.

关键词： Medical genomics Next-generation sequencing

来源：评论

学校读者我要写书评

暂无评论

Wolfram-like syndrome with bicuspid aortic valve due to a homozygous missense variant in CDK13

引用

JOURNAL OF HUMAN GENETICS 2021年第10期66卷 1009-1018页

作者： Acharya, Anushree Raza, Syed Irfan Anwar, Muhammad Zeeshan Bharadwaj, Thashi Liaqat, Khurram Khokhar, Muhammad Akram Shahzad Everard, Jenna L. Nasir, Abdul Nickerson, Deborah A. Bamshad, Michael J. Ansar, Muhammad schrauwen, isabelle Ahmad, Wasim Leal, Suzanne M. Columbia Univ Gertrude H Sergievsky Ctr Ctr Stat Genet Med Ctr New York NY 10027 USA Columbia Univ Dept Neurol Med Ctr New York NY 10027 USA Quaid I Azam Univ Fac Biol Sci Dept Biochem Islamabad Pakistan HBS Med & Dent Coll Dept Biochem Islamabad Pakistan CMH Kharian Med Coll Dept Biochem Punjab Pakistan Major Shabbir Sharif Shaheed Hosp THQ Level Gujrat Punjab Pakistan Ajou Univ Dept Mol Sci & Technol Synthet Prot Engn Lab SPEL Suwon South Korea Univ Washington Dept Genome Sci Seattle WA 98195 USA Univ Washington Dept Pediat Seattle WA 98195 USA Columbia Univ Taub Inst Alzheimers Dis & Aging Brain Med Ctr New York NY 10027 USA

Background Wolfram syndrome (WFS) is characterized by deafness, diabetes mellitus, and diabetes insipidus along with optic atrophy. WFS has an autosomal recessive mode of inheritance and is due to variants in WFS1 and CISD2. Methods We evaluated the underlying molecular etiology of three affected members of a consanguineous family with hearing impairment, bicuspid aortic valve, diabetes mellitus and insipidus, clinodactyly, and gastrointestinal tract abnormalities via exome sequencing approach. We correlated clinical and imaging data with the genetic findings and their associated phenotypes. Results We identified a homozygous missense variant p.(Asn1097Lys) in CDK13, a gene previously associated with autosomal dominant congenital heart defects, dysmorphic facial features, clinodactyly, gastrointestinal tract abnormalities, intellectual developmental disorder, and seizures with variable phenotypic features. Conclusion We report a homozygous variant in CDK13 and suggest that this gene causes an autosomal recessive disorder with hearing impairment, bicuspid aortic valve, diabetes mellitus and insipidus, clinodactyly, and gastrointestinal tract abnormalities.

关键词： Consanguinity Genetic linkage study Human Genetics Molecular Medicine Gene Function Gene Expression Gene Therapy

来源：评论

学校读者我要写书评

暂无评论

Further confirmation of the association of SLC12A2 with non-syndromic autosomal-dominant hearing impairment

引用

JOURNAL OF HUMAN GENETICS 2021年第12期66卷 1169-1175页

作者： Adadey, Samuel M. schrauwen, isabelle Aboagye, Elvis Twumasi Bharadwaj, Thashi Esoh, Kevin K. Basit, Sulman Acharya, Anushree Nouel-Saied, Liz M. Liaqat, Khurram Wonkam-Tingang, Edmond Mowla, Shaheen Awandare, Gordon A. Ahmad, Wasim Leal, Suzanne M. Wonkam, Ambroise Univ Ghana West African Ctr Cell Biol Infect Pathogens WACCB Accra Ghana Univ Cape Town Fac Hlth Sci Div Human Genet Cape Town South Africa Columbia Univ Gertrude H Sergievsky Ctr Ctr Stat Genet Med Ctr New York NY 10027 USA Columbia Univ Dept Neurol Med Ctr New York NY 10027 USA Taibah Univ Al Madinah Al Munawarah Ctr Genet & Inherited Dis Al Munawarah Saudi Arabia Quaid I Azam Univ Fac Biol Sci Dept Biotechnol Islamabad Pakistan Univ Cape Town Fac Hlth Sci Dept Pathol Div Haematol Cape Town South Africa Quaid I Azam Univ Fac Biol Sci Dept Biochem Islamabad Pakistan Columbia Univ Med Ctr Taub Inst Alzheimers Dis & Aging Brain New York NY 10027 USA

Congenital hearing impairment (HI) is genetically heterogeneous making its genetic diagnosis challenging. Investigation of novel HI genes and variants will enhance our understanding of the molecular mechanisms and to aid genetic diagnosis. We performed exome sequencing and analysis using DNA samples from affected members of two large families from Ghana and Pakistan, segregating autosomal-dominant (AD) non-syndromic HI (NSHI). Using in silico approaches, we modeled and evaluated the effect of the likely pathogenic variants on protein structure and function. We identified two likely pathogenic variants in SLC12A2, c.2935G>A:p.(E979K) and c.2939A>T:p.(E980V), which segregate with NSHI in a Ghanaian and Pakistani family, respectively. SLC12A2 encodes an ion transporter crucial in the homeostasis of the inner ear endolymph and has recently been reported to be implicated in syndromic and non-syndromic HI. Both variants were mapped to alternatively spliced exon 21 of the SLC12A2 gene. Exon 21 encodes for 17 residues in the cytoplasmatic tail of SLC12A2, is highly conserved between species, and preferentially expressed in cochlear tissues. A review of previous studies and our current data showed that out of ten families with either AD non-syndromic or syndromic HI, eight (80%) had variants within the 17 amino acid residue region of exon 21 (48 bp), suggesting that this alternate domain is critical to the transporter activity in the inner ear. The genotypic spectrum of SLC12A2 was expanded and the involvement of SLC12A2 in ADNSHI was confirmed. These results also demonstrate the role that SLC12A2 plays in ADNSHI in diverse populations including sub-Saharan Africans.

关键词： Disease genetics Neurological disorders Human Genetics Molecular Medicine Gene Function Gene Expression Gene Therapy

来源：评论

学校读者我要写书评

暂无评论

Exome Sequencing of Two Siblings with Sporadic Autism Spectrum Disorder and Severe Speech Sound Disorder Suggests Pleiotropic and Complex Effects

引用

BEHAVIOR GENETICS 2019年第4期49卷 399-414页

作者： Peter, Beate Dinu, Valentin Liu, Li Huentelman, Matthew Naymik, Marcus Lancaster, Hope Vose, Caitlin schrauwen, isabelle Arizona State Univ Dept Speech & Hearing Sci 975 S Myrtle Ave Tempe AZ 85287 USA St Louis Univ Dept Commun Sci & Disorders St Louis MO 63103 USA Arizona State Univ Dept Biomed Informat Tempe AZ USA Translat Genom Res Inst Neurogen Div Phoenix AZ USA Baylor Coll Med Dept Mol & Human Genet Ctr Stat Genet Houston TX 77030 USA

Recent studies of autism spectrum disorder (ASD) and childhood apraxia of speech (CAS) have resulted in conflicting conclusions regarding the comorbidity of these disorders on phenotypic grounds. In a nuclear family with two dually affected and one unaffected offspring, whole-exome sequences were evaluated for single nucleotide and indel variants and CNVs. The affected siblings but not the unaffected sibling share a rare deleterious compound heterozygous mutation in WWOX, implicated both in ASD and motor control. In addition, one of the affected children carries a rare deleterious de novo mutation in the ASD candidate gene RIMS1. The two affected children but not their unaffected sibling inherited deleterious variants with relevance for ASD and/or CAS. WWOX, RIMS1, and several of the genes harboring the inherited variants are expressed in the brain during prenatal and early postnatal development. Results suggest compound heterozygosity as a cause of ASD and CAS, pleiotropic gene effects, and potentially additional, complex genetic effects.

关键词： Autism spectrum disorder Childhood apraxia of speech Complex trait Comorbidity Heterogeneity Language impairment Multiple hits

来源：评论

学校读者我要写书评

暂无评论

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

请选择保存的检索档案：

请选择收藏分类：

通借通还

建议与咨询 留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

请选择保存的检索档案： 新增检索档案 确定 取消

请选择收藏分类： 新增自定义分类 确定 取消

通借通还

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

请选择保存的检索档案：

请选择收藏分类：