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6 results on '"Yesil, Gozde"'

1. HMZDupFinder: a robust computational approach for detecting intragenic homozygous duplications from exome sequencing data.

Author

Du H, Dardas Z, Jolly A, Grochowski CM, Jhangiani SN, Li H, Muzny D, Fatih JM, Yesil G, Elçioglu NH, Gezdirici A, Marafi D, Pehlivan D, Calame DG, Carvalho CMB, Posey JE, Gambin T, Coban-Akdemir Z, and Lupski JR

Subjects
Humans, Adaptor Proteins, Signal Transducing, Homozygote, Rare Diseases genetics, DNA Copy Number Variations, Exome Sequencing, Software
Abstract

Homozygous duplications contribute to genetic disease by altering gene dosage or disrupting gene regulation and can be more deleterious to organismal biology than heterozygous duplications. Intragenic exonic duplications can result in loss-of-function (LoF) or gain-of-function (GoF) alleles that when homozygosed, i.e. brought to homozygous state at a locus by identity by descent or state, could potentially result in autosomal recessive (AR) rare disease traits. However, the detection and functional interpretation of homozygous duplications from exome sequencing data remains a challenge. We developed a framework algorithm, HMZDupFinder, that is designed to detect exonic homozygous duplications from exome sequencing (ES) data. The HMZDupFinder algorithm can efficiently process large datasets and accurately identifies small intragenic duplications, including those associated with rare disease traits. HMZDupFinder called 965 homozygous duplications with three or less exons from 8,707 ES with a recall rate of 70.9% and a precision of 16.1%. We experimentally confirmed 8/10 rare homozygous duplications. Pathogenicity assessment of these copy number variant alleles allowed clinical genomics contextualization for three homozygous duplications alleles, including two affecting known OMIM disease genes EDAR (MIM# 224900), TNNT1(MIM# 605355), and one variant in a novel candidate disease gene: PAAF1., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Published
2024
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2. Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease.

Author

Jolly A, Bayram Y, Turan S, Aycan Z, Tos T, Abali ZY, Hacihamdioglu B, Coban Akdemir ZH, Hijazi H, Bas S, Atay Z, Guran T, Abali S, Bas F, Darendeliler F, Colombo R, Barakat TS, Rinne T, White JJ, Yesil G, Gezdirici A, Gulec EY, Karaca E, Pehlivan D, Jhangiani SN, Muzny DM, Poyrazoglu S, Bereket A, Gibbs RA, Posey JE, and Lupski JR

Subjects
Cell Cycle Proteins genetics, Cohort Studies, DNA Helicases genetics, DNA-Binding Proteins genetics, Female, Gene Frequency, Humans, Hypogonadism genetics, Immunoglobulins genetics, Minichromosome Maintenance Proteins genetics, Primary Ovarian Insufficiency etiology, Primary Ovarian Insufficiency genetics, Exome Sequencing
Abstract

Context: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hypergonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait., Objective: To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI., Design, Setting, and Participants: We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity., Results: This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds., Conclusions: ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI., (Copyright © 2019 Endocrine Society.)

Published
2019
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3. Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease

Author

Serap Turan, Zeynep Coban Akdemir, Angad Jolly, Firdevs Bas, Davut Pehlivan, Hadia Hijazi, Zehra Yavas Abali, Tuula Rinne, Jennifer E. Posey, Yavuz Bayram, Tahsin Stefan Barakat, Tulay Tos, Roberto Colombo, Shalini N. Jhangiani, Gozde Yesil, Sukran Poyrazoglu, Zeynep Atay, Alper Gezdirici, James R. Lupski, Donna M. Muzny, Tulay Guran, Zehra Aycan, Richard A. Gibbs, Elif Yilmaz Gulec, Janson White, Serpil Bas, Ender Karaca, Feyza Darendeliler, Abdullah Bereket, Bülent Hacıhamdioğlu, Saygin Abali, İstinye Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Bülent Hacıhamdioğlu / 0000-0001-7070-6429, Hacihamdioglu, Bulent, Bülent Hacıhamdioğlu / GBK-6773-2022, Bülent Hacıhamdioğlu / 22134579900, Clinical Genetics, YEŞİL, Gözde, Jolly, Angad, Bayram, Yavuz, Turan, Serap, Aycan, Zehra, Tos, Tulay, Abali, Zehra Yavas, Akdemir, Zeynep Hande Coban, Hijazi, Hadia, Bas, Serpil, Atay, Zeynep, Guran, Tulay, Abali, Saygin, Bas, Firdevs, Darendeliler, Feyza, Colombo, Roberto, Barakat, Tahsin Stefan, Rinne, Tuula, White, Janson J., Yesil, Gozde, Gezdirici, Alper, Gulec, Elif Yilmaz, Karaca, Ender, Pehlivan, Davut, Jhangiani, Shalini N., Muzny, Donna M., Poyrazoglu, Sukran, Bereket, Abdullah, Gibbs, Richard A., Posey, Jennifer E., and Lupski, James R.

Subjects
MECHANISM, 0301 basic medicine, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, PROTEIN, Cell Cycle Proteins, Disease, Primary Ovarian Insufficiency, VARIANTS, Biochemistry, Cohort Studies, 0302 clinical medicine, Endocrinology, Gene Frequency, Locus heterogeneity, FAILURE, Exome sequencing, Jolly A., Bayram Y., Turan S., Aycan Z., Tos T., Abali Z. Y. , Hacihamdioglu B., Akdemir Z. H. C. , Hijazi H., Bas S., et al., -Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease-, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, cilt.104, ss.3049-3067, 2019, Genetics, 030219 obstetrics & reproductive medicine, Minichromosome Maintenance Proteins, REARRANGEMENTS, Oligogenic Inheritance, DNA-Binding Proteins, INSIGHTS, Female, medicine.medical_specialty, Immunoglobulins, Locus (genetics), Genomics, Biology, 03 medical and health sciences, Hypergonadotropic hypogonadism, All institutes and research themes of the Radboud University Medical Center, Internal medicine, Exome Sequencing, medicine, Humans, HOP2-MND1, Settore BIO/10 - BIOCHIMICA, Allele frequency, Clinical Research Articles, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], IDENTIFICATION, MUTATIONS, Hypogonadism, Biochemistry (medical), DNA Helicases, medicine.disease, GENE, 030104 developmental biology, exome
Abstract

Context: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hyper-gonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait. Objective: To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI. Design, Setting, and Participants: We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity. Results: This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds. Conclusions: ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI. National Human Genome Research Institute (NHGRI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI); National Heart Lung and Blood Institute (NHBLI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [UM1 HG006542]; National Institute of Neurologic Disorders and Stroke (NINDS)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R35NS105078]; NHGRIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08 HG008986, U54HG003273]; Howard Hughes Medical Research Fellows Program; Baylor College of Medicine Medical Scientist Training Program; Clinical Research Training Scholarship in Neuromuscular Disease; American Academy of Neurology (AAN); American Brain Foundation (ABF); Netherlands Organization for Scientific Research (ZonMW Veni)Netherlands Organization for Scientific Research (NWO) [91617021]; NARSAD Young Investigator Grant from the Brain & Behavior Research FoundationNARSAD; Muscle Study Group (MSG) This study was supported in part by the National Human Genome Research Institute (NHGRI) and National Heart Lung and Blood Institute (NHBLI) to the Baylor-Hopkins Center for Mendelian Genomics (BHCMG; UM1 HG006542 to J.R.L.); NHGRI grant to Baylor College of Medicine Human Genome Sequencing Center (U54HG003273 to R.A.G.), and National Institute of Neurologic Disorders and Stroke (NINDS; R35NS105078 to J.R.L.). J.E.P. was supported by NHGRI K08 HG008986. A.J. was supported in part by the Howard Hughes Medical Research Fellows Program and the Baylor College of Medicine Medical Scientist Training Program. D. P. is supported by Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Academy of Neurology (AAN), American Brain Foundation (ABF), and Muscle Study Group (MSG). T.S.B. was supported by the Netherlands Organization for Scientific Research (ZonMW Veni, Grant 91617021) and by an NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. WOS:000482558500001 31042289 Q1

Published
2019

4. The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance

Author

Maja Hempel, Jennifer E. Posey, Yavuz Bayram, Eric Boerwinkle, Katta M. Girisha, Ender Karaca, Timur Yildirim, Anju Shukla, Jaya Punetha, Ilhan A. Bayhan, Harsha Doddapaneni, Christopher M. Grochowski, Davut Gul, Aysegul Bursali, Davut Pehlivan, Elif Yilmaz Gulec, Richard A. Gibbs, Zeynep Ocak, Jawid M Fatih, Ibrahim Sahin, Gozde Yesil, Burhan Balta, Onur Yildiz, Alper Gezdirici, Tatjana Bierhals, James R. Lupski, Zafer Yüksel, Hatice Mutlu Albayrak, Donna M. Muzny, Jianhong Hu, Fatma Silan, Zeynep Coban Akdemir, Shen Gu, Öztürk Özdemir, Haktan Bağış Erdem, Periyasamy Radhakrishnan, Burcu Tabakci, Beyhan Tüysüz, Nilay Güneş, Shalini N. Jhangiani, Osman Yeşilbaş, Yavuz Sahin, Nursel Elcioglu, Muhsin Elmas, Konstantinos Tsiakas, Sedat Isikay, Pehlivan, Davut, Bayram, Yavuz, Gunes, Nilay, Akdemir, Zeynep Coban, Shukla, Anju, Bierhals, Tatjana, Tabakci, Burcu, Sahin, Yavuz, Gezdirici, Alper, Fatih, Jawid M., Gulec, Elif Yilmaz, Yesil, Gozde, Punetha, Jaya, Ocak, Zeynep, Grochowski, Christopher M., Karaca, Ender, Albayrak, Hatice Mutlu, Radhakrishnan, Periyasamy, Erdem, Haktan Bagis, Sahin, Ibrahim, Yildirim, Timur, Bayhan, Ilhan A., Bursali, Aysegul, Elmas, Muhsin, Yuksel, Zafer, Ozdemir, Ozturk, Silan, Fatma, Yildiz, Onur, Yesilbas, Osman, Isikay, Sedat, Balta, Burhan, Gu, Shen, Jhangiani, Shalini N., Doddapaneni, Harsha, Hu, Jianhong, Muzny, Donna M., Boerwinkle, Eric, Gibbs, Richard A., Tsiakas, Konstantinos, Hempel, Maja, Girisha, Katta Mohan, Gul, Davut, Posey, Jennifer E., Elcioglu, Nursel H., Tuysuz, Beyhan, Lupski, James R., HKÜ, Sağlık Bilimleri Fakültesi, Fizyoterapi ve Rehabilitasyon Bölümü, YEŞİL, Gözde, İÜC, Cerrahpaşa Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, and OMÜ

Subjects
Male, 0301 basic medicine, Multifactorial Inheritance, Candidate gene, Vesicular Transport Proteins, DE-NOVO, DISEASE, Cohort Studies, MYOPATHY, MULTIPLEX CONGENITA, SKELETAL-MUSCLE, MUTATIONS, PATIENT, FAT1, MECHANISMS, DELETION, 0302 clinical medicine, Candidate Genes and Further Evidence for Oligogenic Inheritance-, AMERICAN JOURNAL OF HUMAN GENETICS, cilt.105, ss.132-150, 2019 [Pehlivan D., Bayram Y., Gunes N., Akdemir Z. C. , Shukla A., Bierhals T., TABAKCI B., Sahin Y., Gezdirici A., Fatih J. M. , et al., -The Genomics of Arthrogryposis, a Complex Trait], Connectin, Copy-number variation, Child, Genetics (clinical), Exome sequencing, Arthrogryposis, Genetics, Mosaicism, Oligogenic Inheritance, Genomics, Pedigree, 3. Good health, Child, Preschool, Female, medicine.symptom, Adult, Genetic Markers, Adolescent, DNA Copy Number Variations, Gestational Age, Locus (genetics), Biology, Article, Young Adult, 03 medical and health sciences, Exome Sequencing, medicine, Humans, Genetic heterogeneity, Infant, Newborn, Infant, Ryanodine Receptor Calcium Release Channel, 030104 developmental biology, Mutation, 030217 neurology & neurosurgery, Comparative genomic hybridization
Abstract

Erdem, Haktan Bagis/0000-0002-4391-1387; Albayrak, Hatice Mutlu/0000-0001-5624-3878; isikay, sedat/0000-0003-0103-9612; Grochowski, Christopher/0000-0002-3884-7720; Gezdirici, Alper/0000-0002-2432-9279; KM, Girisha/0000-0002-0139-8239; Gu, Shen/0000-0003-3107-1218; YESIL, GOZDE/0000-0003-1964-6306; Gezdirici, Alper/0000-0002-2432-9279; Tuysuz, Beyhan/0000-0002-9620-5021; Fatih, Jawid/0000-0002-3927-2711; YUKSEL, Zafer/0000-0002-2085-5773; Balta, Burhan/0000-0003-2672-2493; Posey, Jennifer/0000-0003-4814-6765; Bayhan, Ilhan/0000-0001-8308-1309; Punetha, Jaya/0000-0002-6774-4464; YILDIRIM, Timur/0000-0003-0291-7632 WOS:000473723000011 PubMed ID: 31230720 Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members. National Human Genome Research Institute (NHGRI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [UM1 HG006542]; National Heart, Lung, and Blood Institute (NHLBI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [UM1 HG006542]; NHGRIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08 HG008986]; National Institutes of Health - Brain Disorders and Development Training Grant [T32 NS043124-17]; Clinical Research Training Scholarship in Neuromuscular Disease; Tubitak project, TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [217S675]; Indian Council of Medical Research, New Delhi, IndiaIndian Council of Medical Research (ICMR) [5/13/58/2015/NCD-III]; [R35 NS105078]; [512848]; NATIONAL HUMAN GENOME RESEARCH INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08HG008986, UM1HG006542, K08HG008986, UM1HG006542, UM1HG006542, UM1HG006542, K08HG008986, UM1HG006542] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R35NS105078, T32NS043124, T32NS043124, T32NS043124, R35NS105078, T32NS043124, T32NS043124, R35NS105078, T32NS043124, T32NS043124, T32NS043124, R35NS105078] Funding Source: NIH RePORTER This work was supported in part by R35 NS105078 and MDA#512848 to J.R.L. and a jointly funded National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI) grant to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542). J.E.P. is supported by NHGRI K08 HG008986. D.P. is supported by the National Institutes of Health - Brain Disorders and Development Training Grant (T32 NS043124-17) and a Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Brain Foundation (ABF) and Muscle Study Group (MSG). This study is partly funded by Tubitak project number 217S675, Turkey to N.E. and B.T.. This study is partly funded by Indian Council of Medical Research, New Delhi, India with File no.: No. 5/13/58/2015/NCD-III to A.S.

Published
2019

5. Homozygous Loss-of-function Mutations inSOHLH1in Patients With Nonsyndromic Hypergonadotropic Hypogonadism

Author

Ming Lee, Tom Walsh, Mehmed M. Atik, Yavuz Bayram, Serap Turan, Davut Pehlivan, Tulay Guran, Ece Böber, Mary Claire King, Richard A. Gibbs, Hilal Unal Gulsuner, James R. Lupski, Ayhan Abaci, Ender Karaca, Suleyman Gulsuner, Sarah B. Pierce, Gozde Yesil, Atilla Büyükgebiz, Shalini N. Jhangiani, Abdullah Bereket, Tomasz Gambin, Donna M. Muzny, Eric Boerwinkle, Zeynep Atay, Bayram, Yavuz, Gulsuner, Suleyman, Guran, Tulay, Abaci, Ayhan, Yesil, Gozde, Gulsuner, Hilal Unal, Atay, Zeynep, Pierce, Sarah B., Gambin, Tomasz, Lee, Ming, Turan, Serap, Bober, Ece, Atik, Mehmed M., Walsh, Tom, Karaca, Ender, Pehlivan, Davut, Jhangiani, Shalini N., Muzny, Donna, Bereket, Abdullah, Buyukgebiz, Atilla, Boerwinkle, Eric, Gibbs, Richard A., King, Mary-Claire, Lupski, James R., and YEŞİL, Gözde

Subjects
endocrine system, medicine.medical_specialty, Adolescent, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, TRANSFER-RNA SYNTHETASE, Context (language use), Biology, Biochemistry, PREMATURE OVARIAN FAILURE, Endocrinology, Hypergonadotropic hypogonadism, Internal medicine, Basic Helix-Loop-Helix Transcription Factors, medicine, Humans, Exome, TRANSCRIPTION FACTOR, Child, Loss function, Exome sequencing, GENE-EXPRESSION, JCEM Online: Advances in Genetics, HEARING-LOSS, Hypogonadism, SOHLH1, Homozygote, Biochemistry (medical), PERRAULT SYNDROME, OOGENESIS, medicine.disease, Sex steroid, Mutation, Chromosome abnormality, FOLLICULOGENESIS, Female, Gonadotropin, STEM-CELLS, DYSGENESIS
Abstract

Copyright © 2015 by the Endocrine Society.Context: Hypergonadotropic hypogonadism presents in females with delayed or arrested puberty, primary or secondary amenorrhea due to gonadal dysfunction, and is further characterized by elevated gonadotropins and low sex steroids. Chromosomal aberrations and various specific gene defects can lead to hypergonadotropic hypogonadism. Responsible genes include those with roles in gonadal development or maintenance, sex steroid synthesis, or end-organ resistance to gonadotropins. Identification of novel causative genes in this disorder will contribute to our understanding of the regulation of human reproductive function. Objectives: The aim of this study was to identify and report the gene responsible for autosomal-recessive hypergonadotropic hypogonadism in two unrelated families. Design and Participants: Clinical evaluation and whole-exome sequencing were performed in two pairs of sisters with nonsyndromic hypergonadotropic hypogonadism from two unrelated families. Results: Exome sequencing analysis revealed two different truncating mutations in the same gene: SOHLH1 c.705delT (p.Pro235fs∗4) and SOHLH1 c.27C>G (p.Tyr9stop). Both mutations were unique to the families and segregation was consistent with Mendelian expectations for an autosomal-recessive mode of inheritance. Conclusions: Sohlh1 was known from previous mouse studies to be a transcriptional regulator that functions in the maintenance and survival of primordial ovarian follicles, but loss-of-function mutations in human females have not been reported. Our results provide evidence that homozygous-truncating mutations in SOHLH1 cause female nonsyndromic hypergonadotropic hypogonadism.

Published
2015

6. Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease

Author

Asuman Koparir, Ender Karaca, Tulay Guran, Nursel Elcioglu, Salih Coşkun, Özlem Sezer, Sevcan Tug Bozdogan, Alper Han Cebi, Jill V. Hunter, James R. Lupski, Shalini N. Jhangiani, Sedat Işıkay, Hatip Aydin, Erkan Koparir, Dilek Aktas, Adnan Yuksel, Davut Gul, Mehmed M. Atik, Burak Durmaz, Mehmet Ture, Ian M. Campbell, Wendy K. Chung, Tamar Harel, Emre Kirat, Mahmut Selman Yildirim, Ayse Aksoy, Mehmet Bugrahan Duz, John D. Overton, Tulay Tos, Claudia Gonzaga-Jauregui, Darryl C. De Vivo, Yavuz Bayram, Kadri Karaer, Gozde Yesil, Wojciech Wiszniewski, Davut Pehlivan, Eric Boerwinkle, Huseyin Aslan, Hakan Ulucan, Ozgur Cogulu, Fatma Ekici, Vehap Topcu, Elif Fenercioglu, Mehmet Seven, Alper Gezdirici, Salih Cicek, Tomasz Gambin, Tahsin Yakut, Mustafa Ozen, Mevlit Ikbal, Donna M. Muzny, Zeynep Coban Akdemir, Elif Yilmaz Gulec, Preti Jain, Bilge Geckinli, Sukru Candan, Richard A. Gibbs, Serkan Erdin, Mehmet Alikasifoglu, Ozge Ozalp Yuregir, Ferda Ozkinay, Hilde Van Esch, David R. Adams, Bo Yuan, YEŞİL, Gözde, Ege Üniversitesi, Biruni Üniversitesi, Karaca, Ender, Harel, Tamar, Pehlivan, Davut, Jhangiani, Shalini N., Gambin, Tomasz, Akdemir, Zeynep Coban, Gonzaga-Jauregui, Claudia, Erdin, Serkan, Bayram, Yavuz, Campbell, Ian M., Hunter, Jill V., Atik, Mehmed M., Van Esch, Hilde, Yuan, Bo, Wiszniewski, Wojciech, Isikay, Sedat, Yesil, Gozde, Yuregir, Ozge O., Bozdogan, Sevcan Tug, Aslan, Huseyin, Aydin, Hatip, Tos, Tulay, Aksoy, Ayse, De Vivo, Darryl C., Jain, Preti, Geckinli, B. Bilge, Sezer, Ozlem, Gul, Davut, Durmaz, Burak, Cogulu, Ozgur, Ozkinay, Ferda, Topcu, Vehap, Candan, Sukru, Cebi, Alper Han, Ikbal, Mevlit, Gulec, Elif Yilmaz, Gezdirici, Alper, Koparir, Erkan, Ekici, Fatma, Coskun, Salih, Cicek, Salih, Karaer, Kadri, Koparir, Asuman, Duz, Mehmet Bugrahan, Kirat, Emre, Fenercioglu, Elif, Ulucan, Hakan, Seven, Mehmet, Guran, Tulay, Elcioglu, Nursel, Yildirim, Mahmut Selman, Aktas, Dilek, Alikasifoglu, Mehmet, Ture, Mehmet, Yakut, Tahsin, Overton, John D., Yuksel, Adnan, Ozen, Mustafa, Muzny, Donna M., Adams, David R., Boerwinkle, Eric, Chung, Wendy K., Gibbs, Richard A., and Lupski, James R.

Subjects
Male, PONTOCEREBELLAR HYPOPLASIA, Candidate gene, Rna Helicases, PROTEIN, Cohort Studies, 0302 clinical medicine, Snx14 Cause, Databases, Genetic, Gene Regulatory Networks, Copy-number variation, Pontocerebellar Hypoplasia, Exome sequencing, Alzheimers-Disease, Genetics, 0303 health sciences, H-Prune, General Neuroscience, Brain, Mendelian Randomization Analysis, Neurologic Disease, Pedigree, 3. Good health, ALZHEIMERS-DISEASE, H-PRUNE, symbols, Female, Mutations, Neuroscience(all), SNX14 CAUSE, Biology, TRIPLE T COMPLEX, Article, 03 medical and health sciences, symbols.namesake, Genetic variation, CHROMATIN REMODELING COMPLEX, Humans, Allele, Gene, Genetic Association Studies, 030304 developmental biology, RNA HELICASES, MUTATIONS, Protein, Genetic Variation, Triple T Complex, INTELLECTUAL-DISABILITY SYNDROME, Intellectual-Disability Syndrome, Mendelian inheritance, Chromatin Remodeling Complex, Nervous System Diseases, 030217 neurology & neurosurgery
Abstract

WOS: 000365765400011, PubMed ID: 26539891, Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations., U.S. National Human Genome Research Institute (NHGRI) NHLBI grant [U54HG006542]; NINDSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [RO1 NS058529, K23NS078056]; NHGRIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [5U54HG003273]; Medical Genetics Research Fellowship Program [T32 GM07526]; Regeneron, We thank all the family members and collaborators who participated in this study. This work was supported by U.S. National Human Genome Research Institute (NHGRI) NHLBI grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, NINDS grant RO1 NS058529 to J. R. L., and NHGRI 5U54HG003273 to R. A. G. T. H. is supported by the Medical Genetics Research Fellowship Program (T32 GM07526). W. W. is supported by Career Development Award K23NS078056 from NINDS. The authors would like to thank the ExAC and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about. J.R.L. has stock ownership in 23andMe and Lasergen and is a paid consultant for Regeneron. J. R. L. is also a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the Medical Genetics Laboratory (https://www.bcm.edu/geneticlabs/). W. K. C. is a paid consultant for Regeneron and BioReference Laboratories. C.G.-J. and J. D. O. are employees of the RGC.

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