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Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

HUMAN MUTATION 2019年第1期40卷 53-72页

作者： Richard, Elodie M. Santos-Cortez, Regie Lyn P. Faridi, Rabia Rehman, Atteeq U. Lee, Kwanghyuk Shahzad, Mohsin Acharya, Anushree Khan, Asma A. Imtiaz, Ayesha Chakchouk, Imen Takla, Christina Abbe, Izoduwa Rafeeq, Maria Liaqat, Khurram Chaudhry, Taimur Bamshad, Michael J. Nickerson, Deborah A. schrauwen, isabelle Khan, Shaheen N. Morell, Robert J. Zafar, Saba Ansar, Muhammad Ahmed, Zubair M. Ahmad, Wasim Riazuddin, Sheikh Friedman, Thomas B. Leal, Suzanne M. Riazuddin, Saima Univ Maryland Sch Med Dept Otorhinolaryngol Head & Neck Surg Baltimore MD 21201 USA Baylor Coll Med Dept Mol & Human Genet Ctr Stat Genet Houston TX 77030 USA Natl Inst Deafness & Other Commun Disorders Lab Mol Genet NIH Bethesda MD 20892 USA Univ Punjab Natl Ctr Excellence Mol Biol Lahore Pakistan Shaheed Zulfiqar Ali Bhutto Med Univ Pakistan Inst Med Sci Islamabad Pakistan Quaid I Azam Univ Fac Biol Sci Dept Biotechnol Islamabad Pakistan Univ Washington Dept Genome Sci Seattle WA 98195 USA Natl Inst Deafness & Other Commun Disorders Genom & Computat Biol Core NIH Bethesda MD USA Bahauddin Zakariya Univ Inst Mol Biol & Biotechnol Multan Pakistan Quaid I Azam Univ Fac Biol Sci Dept Biochem Islamabad Pakistan Univ Hlth Sci Allama Iqbal Med Coll Lahore Pakistan

Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome-wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 70 (42.9%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL-associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling, and guide application of future gene-based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders.

关键词： allelic heterogeneity autosomal recessive hearing loss deafness DFNB genetic spectrum Pakistan pathogenic variant

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Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis

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GENETICS IN MEDICINE 2019年第5期21卷 1199-1208页

作者： schrauwen, isabelle Valgaeren, Hanne Tomas-Roca, Laura Sommen, Manou Altunoglu, Umut Wesdorp, Mieke Beyens, Matthias Fransen, Erik Nasir, Abdul Vandeweyer, Geert Schepers, Anne Rahmoun, Malika van Beusekom, Ellen Huentelman, Matt J. Offeciers, Erwin Dhooghe, Ingeborg Huber, Alex Van de Heyning, Paul Zanetti, Diego De Leenheer, Els M. R. Gilissen, Christian Hoischen, Alexander Cremers, Cor W. Verbist, Berit de Brouwer, Arjan P. M. Padberg, George W. Pennings, Ronald Kayserili, Hulya Kremer, Hannie Van Camp, Guy van Bokhoven, Hans Univ Antwerp Ctr Med Genet Antwerp Belgium Antwerp Univ Hosp Antwerp Belgium Translat Genom Res Inst Neurogen Div Phoenix AZ USA Radboud Univ Nijmegen Dept Human Genet Med Ctr Nijmegen Netherlands Radboud Univ Nijmegen Donders Inst Brain Cognit & Behav Med Ctr Nijmegen Netherlands Istanbul Univ Istanbul Fac Med Dept Med Genet Istanbul Turkey Radboud Univ Nijmegen Med Ctr Dept Otorhinolaryngol Hearing & Genes Nijmegen Netherlands Radboud Univ Nijmegen Med Ctr Radboud Inst Mol Life Sci Nijmegen Netherlands Ajou Univ Dept Mol Sci & Technol Synthet Prot Engn Lab SPEL Suwon South Korea St Augustinus Hosp Antwerp European Inst ORL Antwerp Belgium Ghent Univ Hosp Dept Otolaryngol Ghent Belgium Univ Hosp Zurich Dept Otorhinolaryngol Head & Neck Surg Zurich Switzerland Univ Antwerp Univ Antwerp Hosp Dept ORL & Head & Neck Surg Edegem Belgium Univ Milan Dept Clin Sci & Community Hlth Osp Maggiore Policlin Audiol UnitIRCCS Fdn Ca Granda Milan Italy Radboud Univ Nijmegen Med Ctr Dept Internal Med Nijmegen Netherlands Radboud Univ Nijmegen Med Ctr Radboud Ctr Infect Dis RCI Nijmegen Netherlands Radboud Univ Nijmegen Med Ctr Dept Radiol & Nucl Med Nijmegen Netherlands Leiden Univ Dept Radiol Med Ctr Leiden Netherlands Radboud Univ Nijmegen Dept Neurol Med Ctr Nijmegen Netherlands KUSOM Dept Med Genet Istanbul Turkey Baylor Coll Med Mol & Human Genet Dept Ctr Stat Genet Houston TX 77030 USA

Purpose: To characterize new molecular factors implicated in a hereditary congenital facial paresis (HCFP) family and otosclerosis. Methods: We performed exome sequencing in a four-generation family presenting nonprogressive HCFP and mixed hearing loss (HL). MEPE was analyzed using either Sanger sequencing or molecular inversion probes combined with massive parallel sequencing in 89 otosclerosis families, 1604 unrelated affected subjects, and 1538 unscreened controls. Results: Exome sequencing in the HCFP family led to the identification of a rare segregating heterozygous frameshift variant p.(Gln425Lysfs*38) in MEPE. As the HL phenotype in this family resembled otosclerosis, we performed variant burden and variance components analyses in a large otosclerosis cohort and demonstrated that nonsense and frameshift MEPE variants were significantly enriched in affected subjects (p = 0.0006-0.0060). Conclusion: MEPE exerts its function in bone homeostasis by two domains, an RGD and an acidic serine aspartate-rich MEPE-associated (ASARM) motif inhibiting respectively bone resorption and mineralization. All variants associated with otosclerosis are predicted to result in nonsense mediated decay or an ASARM-and-RGD-truncated MEPE. The HCFP variant is predicted to produce an ASARM-truncated MEPE with an intact RGD motif. This difference in effect on the protein corresponds with the presumed pathophysiology of both diseases, and provides a plausible molecular explanation for the distinct phenotypic outcome.

关键词： otosclerosis hereditary congenital facial paresis MEPE craniofacial bone disorder hearing loss

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Novel digenic inheritance of PCDH15 and USH1G underlies profound non-syndromic hearing impairment

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BMC MEDICAL GENETICS 2018年第1期19卷 122-122页

作者： schrauwen, isabelle Chakchouk, Imen Acharya, Anushree Liaqat, Khurram Irfanullah Nickerson, Deborah A. Bamshad, Michael J. Shah, Khadim Ahmad, Wasim Leal, Suzanne M. Baylor Coll Med Ctr Stat Genet Dept Mol & Human Genet One Baylor Plaza 700D Houston TX 77030 USA Quaid I Azam Univ Fac Biol Sci Dept Biotechnol Islamabad Pakistan Quaid I Azam Univ Fac Biol Sci Dept Biochem Islamabad Pakistan Univ Washington Dept Genome Sci Seattle WA 98195 USA Univ Washington Dept Pediat Seattle WA 98195 USA

Background: Digenic inheritance is the simplest model of oligenic disease. It can be observed when there is a strong epistatic interaction between two loci. For both syndromic and non-syndromic hearing impairment, several forms of digenic inheritance have been reported. Methods: We performed exome sequencing in a Pakistani family with profound non-syndromic hereditary hearing impairment to identify the genetic cause of disease. Results: We found that this family displays digenic inheritance for two trans heterozygous missense mutations, one in PCDH15 [p.(Arg1034His)] and another in USH1G [p.(Asp365Asn)]. Both of these genes are known to cause autosomal recessive non-syndromic hearing impairment and Usher syndrome. The protein products of PCDH15 and USH1G function together at the stereocilia tips in the hair cells and are necessary for proper mechanotransduction. Epistasis between Pcdh15 and Ush1G has been previously reported in digenic heterozygous mice. The digenic mice displayed a significant decrease in hearing compared to age-matched heterozygous animals. Until now no human examples have been reported. Conclusions: The discovery of novel digenic inheritance mechanisms in hereditary hearing impairment will aid in understanding the interaction between defective proteins and further define inner ear function and its interactome.

关键词： Digenic inheritance Hearing impairment Deafness PCDH15 USH1G

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Front Cover, Volume 41, Issue 2

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Human Mutation 2020年第2期41卷

作者： Carmel G. McCullough Szabolcs Szelinger Newell Belnap Keri Ramsey isabelle schrauwen Ana M. Claasen Leah W. Burke Ashley L. Siniard Matthew J. Huentelman Vinodh Narayanan David W. Craig Department of Translational Genomics University of Southern California Los Angeles California Center for Rare Childhood Disorders Neurogenomics Division Translational Genomics Research Institute Phoenix Arizona Carmel G. McCullough and Szabolcs Szelinger contributed equally scientifically. Department of Pediatrics Larner College of Medicine University of Vermont Burlington Vermont

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A novel FBXO28 frameshift mutation in a child with developmental delay, dysmorphic features, and intractable epilepsy: A second gene that may contribute to the 1q41-q42 deletion phenotype

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AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2018年第7期176卷 1549-1558页

作者： Balak, Chris Belnap, Newell Ramsey, Keri Joss, Shelagh Devriendt, Koen Naymik, Marcus Jepsen, Wayne Siniard, Ashley L. Szelinger, Szabolcs Parker, Mary E. Richholt, Ryan Izatt, Tyler LaFleur, Madison Terraf, Panieh Llaci, Lorida De Both, Matt Piras, Ignazio S. Rangasamy, Sampathkumar schrauwen, isabelle Craig, David W. Huentelman, Matt Narayanan, Vinodh Translat Genom Res Inst Neurogen Div Ctr Rare Childhood Disorders C4RCD 445 N 5th St Phoenix AZ 85004 USA Queen Elizabeth Univ Hosp West Scotland Genet Serv Glasgow Lanark Scotland Univ Leuven Ctr Human Genet Leuven Belgium UCLA Ctr Hlth Sci UCLA Pathol & Lab Med Los Angeles CA USA Texas State Univ Dept Phys Therapy San Marcos TX USA UR Our Hope Undiagnosed & Rare Disorder Org Austin TX USA Baylor Coll Med Ctr Stat Genet Dept Mol & Human Genet Houston TX 77030 USA USC Keck Sch Med Dept Translat Genom Los Angeles CA USA

Chromosome 1q41-q42 deletions have recently been associated with a recognizable neurodevelopmental syndrome of early childhood (OMIM 612530). Within this group, a predominant phenotype of developmental delay (DD), intellectual disability (ID), epilepsy, distinct dysmorphology, and brain anomalies on magnetic resonance imaging/computed tomography has emerged. Previous reports of patients with de novo deletions at 1q41-q42 have led to the identification of an evolving smallest region of overlap which has included several potentially causal genes including DISP1, TP53BP2, and FBXO28. In a recent report, a cohort of patients with de novo mutations in WDR26 was described that shared many of the clinical features originally described in the 1q41-q42 microdeletion syndrome (MDS). Here, we describe a novel germline FBXO28 frameshift mutation in a 3-year-old girl with intractable epilepsy, ID, DD, and other features which overlap those of the 1q41-q42 MDS. Through a familial whole-exome sequencing study, we identified a de novo FBXO28 c.972_973delACinsG (***325GlufsX3) frameshift mutation in the proband. The frameshift and resulting premature nonsense mutation have not been reported in any genomic database. This child does not have a large 1q41-q42 deletion, nor does she harbor a WDR26 mutation. Our case joins a previously reported patient also in whom FBXO28 was affected but WDR26 was not. These findings support the idea that FBXO28 is a monogenic disease gene and contributes to the complex neurodevelopmental phenotype of the 1q41-q42 gene deletion syndrome.

关键词： 1q41q42 chromosome 1q41-q42 deletion syndrome dominant negative F-Box protein 28 FBXO28 intellectual disability SCF complex seizures WDR26

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Whole transcriptome profiling of the human hippocampus suggests an involvement of the KIBRA rs17070145 polymorphism in differential activation of the MAPK signaling pathway

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HIPPOCAMPUS 2017年第7期27卷 784-793页

作者： Piras, Ignazio S. Krate, Jonida schrauwen, isabelle Corneveaux, Jason J. Serrano, Geidy E. Sue, Lucia Beach, Thomas G. Huentelman, Matthew J. Translat Genom Res Inst Neurogenom Div Phoenix AZ 85004 USA Banner Sun Hlth Res Inst Civin Lab Neuropathol Sun City AZ 85351 USA

The rs17070145-T variant of the WWC1 gene, coding for the KIBRA protein, has been associated with both increased episodic memory performance and lowered risk for late onset Alzheimer's disease, although the mechanism behind this protective effect has not been completely elucidated. To achieve a better understanding of the pathways modulated by rs17070145 and its associated functional variant(s), we used laser capture microdissection (LCM) and RNA-sequencing to investigate the effect of rs17070145 genotypes on whole transcriptome expression in the human hippocampus (HP) of 22 neuropathologically normal individuals, with a specific focus on the dentate gyrus (DG) and at the pyramidal cells (PC) of CA1 and CA3 sub-regions. Differential expression analysis of RNA-seq data within the HP based on the rs17070145 genotype revealed an overexpression of genes involved in the MAPK signaling pathway, potentially driven by the T/T genotype. The most important contribution comes from genes dysregulated within the DG region. Other genes significantly dysregulated, and not involved in the MAPK pathway (Adj P< 0.01 and Fold Change>|1.00|) were: RSPO4 (HP);ARC, DUSP5, DNAJB5, EGR4, PPP1R15A, WBP11P1, EGR1, GADD45B (DG);CH25H, HSPA1A, HSPA1B, TNFSF9, and NPAS4 (PC). Several evidences suggested that the MAPK signaling pathway is linked with memory and learning processes. In non-neuronal cells, the KIBRA protein is phosphorylated by ERK1/2 (involved in the MAPK signaling) in cells as well as in vitro. Several of the other dysregulated genes are involved in memory and learning processes, as well as in Alzheimer's Disease. In conclusion, our results suggest that the effect of the WWC1 rs17070145 polymorphism on memory performance and Alzheimer's disease might be due to a differential regulation of the MAPK signaling, a key pathway involved in memory and learning processes.

关键词： dentate gyrus memory pyramidal cells RNAseq WWC1

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Ca²⁺-binding protein 2 inhibits Ca²⁺-channel inactivation in mouse inner hair cells

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2017年第9期114卷 E1717-E1726页

作者： Picher, Maria Magdalena Gehrt, Anna Meese, Sandra Ivanovic, Aleksandra Predoehl, Friederike Jung, SangYong schrauwen, isabelle Dragonetti, Alberto Giulio Colombo, Roberto Van Camp, Guy Strenzke, Nicola Moser, Tobias Univ Med Ctr Goettingen Inst Auditory Neurosci & InnerEarLab D-37099 Gottingen Germany Univ Goettingen Goettingen Grad Sch Neurosci Biophys & Mol Biosci D-37077 Gottingen Germany Univ Goettingen Bernstein Ctr Computat Neurosci D-37077 Gottingen Germany Max Planck Inst Biophys Chem Synapt Nanophysiol Grp D-37077 Gottingen Germany Univ Goettingen Med Ctr Dept Otolaryngol Auditory Syst Physiol Grp InnerEarLab D-37075 Gottingen Germany Max Planck Inst Expt Med D-37075 Gottingen Germany Univ Goettingen Ctr Nanoscale Microscopy & Mol Physiol Brain D-37075 Gottingen Germany Inst Biomed Sci Neuro Modulat & Neuro Circuitry Grp Singapore 138667 Singapore Univ Antwerp Dept Med Genet B-2610 Antwerp Belgium Translat Genom Res Inst Neurogen Div Phoenix AZ 85004 USA Niguarda Ca Granda Metropolitan Hosp Dept Surg Otorhinolaryngol I-20162 Milan Italy Niguarda Ca Granda Metropolitan Hosp Ctr Study Rare Hereditary Dis I-20162 Milan Italy Univ Cattolica Sacro Cuore Inst Clin Biochem I-00198 Rome Italy

Ca2+-binding protein 2 (CaBP2) inhibits the inactivation of heterologously expressed voltage-gated Ca2+ channels of type 1.3 (Ca(V)1.3) and is defective in human autosomal-recessive deafness 93 (DFNB93). Here, we report a newly identified mutation in CABP2 that causes a moderate hearing impairment likely via nonsense-mediated decay of CABP2-mRNA. To study the mechanism of hearing impairment resulting from CABP2 loss of function, we disrupted Cabp2 in mice (Cabp2(LacZ/LacZ)). CaBP2 was expressed by cochlear hair cells, preferentially in inner hair cells (IHCs), and was lacking from the postsynaptic spiral ganglion neurons (SGNs). Cabp2(LacZ/LacZ) mice displayed intact cochlear amplification but impaired auditory brainstem responses. Patch-clamp recordings from Cabp2(LacZ/LacZ) IHCs revealed enhanced Ca2+-channel inactivation. The voltage dependence of activation and the number of Ca2+ channels appeared normal in Cabp2(LacZ/LacZ) mice, as were ribbon synapse counts. Recordings from single SGNs showed reduced spontaneous and sound-evoked firing rates. We propose that CaBP2 inhibits Ca(V)1.3 Ca2+-channel inactivation, and thus sustains the availability of Ca(V)1.3 Ca2+ channels for synaptic sound encoding. Therefore, we conclude that human deafness DFNB93 is an auditory synaptopathy.

关键词： Ca2+ channel inner hair cell ribbon synapse synaptopathy hearing impairment

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Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

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HUMAN GENETICS 2018年第9期137卷 735-752页

作者： Santos-Cortez, Regie Lyn P. Khan, Valeed Khan, Falak Sher Mughal, Zaib-un-Nisa Chakchouk, Imen Lee, Kwanghyuk Rasheed, Memoona Hamza, Rifat Acharya, Anushree Ullah, Ehsan Saqib, Muhammad Arif Nadeem Abbe, Izoduwa Ali, Ghazanfar Hassan, Muhammad Jawad Khan, Saadullah Azeem, Zahid Ullah, Irfan Bamshad, Michael J. Nickerson, Deborah A. schrauwen, isabelle Ahmad, Wasim Ansar, Muhammad Leal, Suzanne M. Baylor Coll Med Dept Mol & Human Genet Ctr Stat Genet 1 Baylor Plaza 700D Houston TX 77030 USA Univ Colorado Sch Med Dept Otolaryngol 12700 E 19th Ave Aurora CO 80045 USA Quaid I Azam Univ Dept Biochem Fac Biol Sci Islamabad 45320 Pakistan Pakistan Hlth Res Council Shahrah E Jamhuriat G-5-2 Islamabad Pakistan Univ Azad Jammu & Kashmir Dept Biotechnol Muzaffarabad Pakistan Natl Univ Sci & Technol Atta Ur Rahman Sch Appl Biosci Dept Healthcare Biotechnol Islamabad Pakistan Kohat Univ Sci & Technol Dept Biotechnol & Genet Engn Kohat Kpk Pakistan Azad Jammu & Kashmir Med Coll Dept Biochem Muzaffarabad Pakistan Univ Washington Dept Genome Sci Foege Bldg S-2503720 15th Ave Seattle WA 98195 USA Univ Washington Dept Pediat 1959 NE Pacific St Seattle WA 98195 USA

Identification of Mendelian genes for neurodevelopmental disorders using exome sequencing to study autosomal recessive (AR) consanguineous pedigrees has been highly successful. To identify causal variants for syndromic and non-syndromic intellectual disability (ID), exome sequencing was performed using DNA samples from 22 consanguineous Pakistani families with ARID, of which 21 have additional phenotypes including microcephaly. To aid in variant identification, homozygosity mapping and linkage analysis were performed. DNA samples from affected family member(s) from every pedigree underwent exome sequencing. Identified rare damaging exome variants were tested for co-segregation with ID using Sanger sequencing. For seven ARID families, variants were identified in genes not previously associated with ID, including: EI24, FXR1 and TET3 for which knockout mouse models have brain defects;and CACNG7 and TRAPPC10 where cell studies suggest roles in important neural pathways. For two families, the novel ARID genes CARNMT1 and GARNL3 lie within previously reported ID microdeletion regions. We also observed homozygous variants in two ID candidate genes, GRAMD1B and TBRG1, for which each has been previously reported in a single family. An additional 14 families have homozygous variants in established ID genes, of which 11 variants are novel. All ARID genes have increased expression in specific structures of the developing and adult human brain and 91% of the genes are differentially expressed in utero or during early childhood. The identification of novel ARID candidate genes and variants adds to the knowledge base that is required to further understand human brain function and development.

关键词： Knowledge Bases Co-segregation whole exome sequencing Novels variants IDAHO OPERATIONS OFFICE family Neural Pathway Intellectual Disability CACNG7 gene cerebral function Family Members

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Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

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GENETICS IN MEDICINE 2021年第11期23卷 2122-2137页

作者： Weerts, Marjolein J. A. Lanko, Kristina Guzman-Vega, Francisco J. Jackson, Adam Ramakrishnan, Reshmi Cardona-Londono, Kelly J. Pena-Guerra, Karla A. van Bever, Yolande van Paassen, Barbara W. Kievit, Anneke van Slegtenhorst, Marjon Allen, Nicholas M. Kehoe, Caroline M. Robinson, Hannah K. Pang, Lewis Banu, Selina H. Zaman, Mashaya Efthymiou, Stephanie Houlden, Henry Jarvela, Irma Lauronen, Leena Maatta, Tuomo schrauwen, isabelle Leal, Suzanne M. Ruivenkamp, Claudia A. L. Barge-Schaapveld, Daniela Q. C. M. Peeters-Scholte, Cacha M. P. C. D. Galehdari, Hamid Mazaheri, Neda Sisodiya, Sanjay M. Harrison, Victoria Sun, Angela Thies, Jenny Pedroza, Luis Alberto Lara-Taranchenko, Yana Chinn, Ivan K. Lupski, James R. Garza-Flores, Alexandra McGlothlin, Jeffery Yang, Lin Huang, Shaoping Wang, Xiaodong Jewett, Tamison Rosso, Gretchen Lin, Xi Mohammed, Shehla Merritt, J. Lawrence, II Mirzaa, Ghayda M. Timms, Andrew E. Scheck, Joshua Elting, Mariet W. Polstra, Abeltje M. Schenck, Lauren Ruzhnikov, Maura R. Z. Vetro, Annalisa Montomoli, Martino Guerrini, Renzo Koboldt, Daniel C. Mosher, Theresa Mihalic Pastore, Matthew T. McBride, Kim L. Peng, Jing Pan, Zou Willemsen, Marjolein Koning, Susanne Turnpenny, Peter D. de Vries, Bert B. A. Gilissen, Christian Pfundt, Rolph Lees, Melissa Braddock, Stephen R. Klemp, Kara C. Vansenne, Fleur van Gijn, Marielle E. Quindipan, Catherine Deardorff, Matthew A. Hamm, J. Austin Putnam, Abbey M. Baud, Rebecca Walsh, Laurence Lynch, Sally A. Baptista, Julia Person, Richard E. Monaghan, Kristin G. Crunk, Amy Keller-Ramey, Jennifer Reich, Adi Elloumi, Houda Zghal Alders, Marielle Kerkhof, Jennifer McConkey, Haley Haghshenas, Sadegheh Maroofian, Reza Sadikovic, Bekim Banka, Siddharth Arold, Stefan T. Barakat, Tahsin Stefan Erasmus MC Univ Med Ctr Dept Clin Genet Rotterdam Netherlands King Abdullah Univ Sci & Technol KAUST Computat Biosci Res Ctr CBRC Div Biol & Environm Sci & Engn Thuwal Saudi Arabia Manchester Univ NHS Fdn Trust Manchester Ctr Genom Med St Marys Hosp Hlth Innovat Manchester Manchester Lancs England Univ Manchester Fac Biol Med & Hlth Sch Biol Sci Div Evolut & Genom Sci Manchester Lancs England Natl Univ Ireland Galway Dept Paediat Galway Ireland Royal Devon & Exeter NHS Fdn Trust Exeter Genom Lab RILD Bldg Exeter Devon England Dr MR Khan Shishu Children Hosp & ICH Dept Pediat Neurol Dhaka Bangladesh UCL Queen Sq Inst Neurol Dept Neuromuscular Disorders London England Univ Helsinki Dept Med Genet Helsinki Finland Univ Helsinki New Childrens Hosp HUS Diagnost Ctr Dept Clin Neurophysiol Helsinki Finland Helsinki Univ Hosp HUH Helsinki Finland Joint Author Kainuu Disabil Serv Kajaani Finland Columbia Univ Ctr Stat Genet Taub Inst Alzheimers Dis & Aging Brain Sergievsky CtrDept NeurolMed Ctr New York NY USA Leiden Univ Med Ctr Dept Clin Genet Leiden Netherlands Leiden Univ Med Ctr Dept Neurol Leiden Netherlands Shahid Chamran Univ Ahvaz Fac Sci Dept Genet Ahvaz Iran UCL Queen Sq Inst Neurol Dept Clin & Expt Epilepsy London England Chalfont Ctr Epilepsy London Bucks England Princess Anne Hosp Wessex Clin Genet Serv Southampton Hants England Univ Washington Sch Med Dept Pediat Div Med Genet Seattle WA 98195 USA Seattle Childrens Hosp Div Med Genet Dept Pediat Seattle WA USA Columbia Univ Dept Pediat Vagelos Coll Phys & Surg Irving Med Ctr New York NY 10027 USA Univ San Francisco Quito Hosp Valles Colegio Ciencias Salud Quito Ecuador Baylor Coll Med Dept Pediat Sect Immunol Allergy & Retrovirol Houston TX 77030 USA Texas Childrens Hosp Houston TX 77030 USA Texas Childrens Hosp Baylor Coll Med Dept Pediat Ctr Human Immunobiol Houston TX 77030 USA Baylor Coll Med Dept Mol & Human Genet Baylor Hopkins Ctr Mendelian Geno

Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

关键词： Biomedicine general Human Genetics Laboratory Medicine

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Identification of CACNA1D variants associated with sinoatrial node dysfunction and deafness in additional Pakistani families reveals a clinical significance

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JOURNAL OF HUMAN GENETICS 2019年第2期64卷 153-160页

作者： Liaqat, Khurram schrauwen, isabelle Laza, Syed Han Lee, Kwanghyuk Hussain, Shabir Chakchouk, Imen Nasir, Abdul Acharya, Anushree Abbe, Izoduwa Umair, Muhammad Ansar, Muhammad Ullah, Han Shah, Khadim Bamshad, Michael J. Nickerson, Deborah A. Ahmad, Wasim Leal, Suzanne M. Anderson, Peter Annable, Marcus Blue, Elizabeth E. Buckingham, Kati J. Chin, Jennifer Chong, Jessica X. Cornejo, Rodolfo, Jr. Davis, Colleen P. Frazar, Christopher Horike-Pyne, Martha Jarvik, Gail P. Johanson, Eric Kang, Ashley N. Kolar, Tom Krauter, Stephanie A. Marvin, Colby T. McGee, Sean McGoldrick, Daniel J. Patterson, Karynne Phillips, Sam W. Pijoan, Jessica Richardson, Matthew A. Robertson, Peggy D. Slattery, Krystal Shively, Kathryn M. Smith, Joshua D. Tackett, Monica Tattersall, Alice E. Wegener, Marc Weiss, Jeffrey M. Wheeler, Marsha M. Yi, Qian Zhang, Di Quaid I Azam Univ Islamabad Fac Biol Sci Dept Biotechnol Islamabad Pakistan Baylor Coll Med Ctr Stat Genet Dept Mol & Human Genet Houston TX 77030 USA Shaheed Zulfiqar Ali Bhutto Med Univ Islamabad HBS Med Coll Dept Biochem Islamabad Pakistan Quaid I Azam Univ Islamabad Fac Biol Sci Dept Biochem Islamabad Pakistan MNGHA KAIMRC Med Genom Res Dept POB 3660 Riyadh 11481 Saudi Arabia Shaheed Benazir Bhutto Univ Dept Chem Sheringal Upper Dir Pakistan Comsats Univ Islamabad Dept Environm Sci Abbottabad Campus Islamabad Pakistan Univ Washington Dept Genome Sci Seattle WA 98195 USA Univ Washington Dept Pediat Seattle WA 98195 USA Univ Washington Seattle WA 98195 USA Seattle Childrens Hosp Seattle WA USA Baylor Coll Med Houston TX 77030 USA

Sinoatrial node dysfunction and deafness (SANDD) syndrome is rare and characterized by a low heart beat and severe-toprofound deafness. Additional features include fatigue, dizziness, and episodic syncope. The sinoatrial node (SAN) drives heart automaticity and continuously regulates heart rate. The CACNA1D gene encoding the Ca(v)1.3 protein expressed in inner hair cells, atria and SAN, induces loss-of-function in channel activity and underlies SANDD. To date, only one variant c.1208_1209insGGG:p.(G403_V404insG) has been reported for SANDD syndrome. We studied five Pakistani families with SANDD and characterized a new missense variant p.(A376V) in CACNA1D in one family, and further characterized the founder variant p.(G403_V404insG) in four additional pedigrees. We show that affected individuals in the four families which segregate p.(G403_V404insG) share a 1.03 MB haplotype on 3p21.1 suggesting they share a common distant ancestor. In conclusion, we identified new and known variants in CACNA1D in five Pakistani families with SANDD. This study is of clinical importance as the CACNA1D founder variant is only observed in families from the Khyber Pakhtunkhwa (KPK) province, in Pakistan. Therefore, screening patients with congenital deafness for SAN dysfunction in this province could ensure adequate follow-up and prevent cardiac failure associated with SAN.

关键词： Medical genomics Next-generation sequencing

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