%0 Journal Article %J HGG Adv %D 2022 %T Developmental genomics of limb malformations: Allelic series in association with gene dosage effects contribute to the clinical variability. %A Duan, Ruizhi %A Hijazi, Hadia %A Gulec, Elif Yilmaz %A Eker, Hatice Koçak %A Costa, Silvia R %A Sahin, Yavuz %A Ocak, Zeynep %A Isikay, Sedat %A Ozalp, Ozge %A Bozdogan, Sevcan %A Aslan, Huseyin %A Elcioglu, Nursel %A Bertola, Debora R %A Gezdirici, Alper %A Du, Haowei %A Fatih, Jawid M %A Grochowski, Christopher M %A Akay, Gulsen %A Jhangiani, Shalini N %A Karaca, Ender %A Gu, Shen %A Coban-Akdemir, Zeynep %A Posey, Jennifer E %A Bayram, Yavuz %A Sutton, V Reid %A Carvalho, Claudia M B %A Pehlivan, Davut %A Richard A Gibbs %A James R Lupski %X

Genetic heterogeneity, reduced penetrance, and variable expressivity, the latter including asymmetric body axis plane presentations, have all been described in families with congenital limb malformations (CLMs). Interfamilial and intrafamilial heterogeneity highlight the complexity of the underlying genetic pathogenesis of these developmental anomalies. Family-based genomics by exome sequencing (ES) and rare variant analyses combined with whole-genome array-based comparative genomic hybridization were implemented to investigate 18 families with limb birth defects. Eleven of 18 (61%) families revealed explanatory variants, including 7 single-nucleotide variant alleles and 3 copy number variants (CNVs), at previously reported "disease trait associated loci": , cluster, , , and . Breakpoint junction analyses for all three CNV alleles revealed mutational signatures consistent with microhomology-mediated break-induced replication, a mechanism facilitated by -mediated rearrangement. Homozygous duplication of was observed in one Turkish kindred and represents a novel contributory genetic mechanism to Gollop-Wolfgang Complex (MIM: 228250), where triplication of the locus has been reported in one family from Japan (i.e., 4n = 2n + 2n versus 4n = 3n + 1n allelic configurations). Genes acting on limb patterning are sensitive to a gene dosage effect and are often associated with an allelic series. We extend an allele-specific gene dosage model to potentially assist, in an adjuvant way, interpretations of interconnections among an allelic series, clinical severity, and reduced penetrance of the -related CLM spectrum.

%B HGG Adv %V 3 %P 100132 %8 2022 Oct 13 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/36035248?dopt=Abstract %R 10.1016/j.xhgg.2022.100132 %0 Journal Article %J Am J Hum Genet %D 2021 %T High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population. %A Mitani, Tadahiro %A Isikay, Sedat %A Gezdirici, Alper %A Gulec, Elif Yilmaz %A Punetha, Jaya %A Fatih, Jawid M %A Herman, Isabella %A Akay, Gulsen %A Du, Haowei %A Calame, Daniel G %A Ayaz, Akif %A Tos, Tulay %A Yesil, Gozde %A Aydin, Hatip %A Geckinli, Bilgen %A Elcioglu, Nursel %A Candan, Sukru %A Sezer, Ozlem %A Erdem, Haktan Bagis %A Gul, Davut %A Demiral, Emine %A Elmas, Muhsin %A Yesilbas, Osman %A Kilic, Betul %A Gungor, Serdal %A Ceylan, Ahmet C %A Bozdogan, Sevcan %A Ozalp, Ozge %A Cicek, Salih %A Aslan, Huseyin %A Yalcintepe, Sinem %A Topcu, Vehap %A Bayram, Yavuz %A Grochowski, Christopher M %A Jolly, Angad %A Dawood, Moez %A Duan, Ruizhi %A Jhangiani, Shalini N %A Harshavardhan Doddapaneni %A Jianhong Hu %A Donna M Muzny %A Marafi, Dana %A Akdemir, Zeynep Coban %A Karaca, Ender %A Carvalho, Claudia M B %A Richard A Gibbs %A Posey, Jennifer E %A James R Lupski %A Pehlivan, Davut %K Adolescent %K Adult %K Child %K Child, Preschool %K Cohort Studies %K Exome Sequencing %K Female %K Genomics %K Humans %K Infant %K Infant, Newborn %K Male %K Middle Aged %K Mutation %K Neurodevelopmental Disorders %K Pedigree %K Phenotype %K Prevalence %K Turkey %K Young Adult %X

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.

%B Am J Hum Genet %V 108 %P 1981-2005 %8 2021 Oct 07 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/34582790?dopt=Abstract %R 10.1016/j.ajhg.2021.08.009 %0 Journal Article %J Am J Hum Genet %D 2017 %T REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis. %A Bayram, Yavuz %A White, Janson J %A Elcioglu, Nursel %A Cho, Megan T %A Zadeh, Neda %A Gedikbasi, Asuman %A Palanduz, Sukru %A Ozturk, Sukru %A Cefle, Kivanc %A Kasapcopur, Ozgur %A Coban Akdemir, Zeynep %A Pehlivan, Davut %A Begtrup, Amber %A Carvalho, Claudia M B %A Paine, Ingrid Sophie %A Mentes, Ali %A Bektas-Kayhan, Kivanc %A Karaca, Ender %A Jhangiani, Shalini N %A Muzny, Donna M %A Gibbs, Richard A %A Lupski, James R %K Adolescent %K Base Sequence %K Chromosome Segregation %K Exons %K Family %K Female %K Fibromatosis, Gingival %K Genetic Predisposition to Disease %K Humans %K Male %K Middle Aged %K Mutation %K Pedigree %K Repressor Proteins %X

Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor (REST) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exon-truncating mutations in REST for organismal development and the association with the HGF phenotype.

%B Am J Hum Genet %V 101 %P 149-156 %8 2017 Jul 06 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/28686854?dopt=Abstract %R 10.1016/j.ajhg.2017.06.006 %0 Journal Article %J Hum Genet %D 2015 %T Exome sequencing reveals homozygous TRIM2 mutation in a patient with early onset CMT and bilateral vocal cord paralysis. %A Pehlivan, Davut %A Coban Akdemir, Zeynep %A Karaca, Ender %A Bayram, Yavuz %A Jhangiani, Shalini %A Yildiz, Edibe Pembegul %A Muzny, Donna %A Uluc, Kayihan %A Gibbs, Richard A %A Elcioglu, Nursel %A Lupski, James R %A Harel, Tamar %K Adult %K Charcot-Marie-Tooth Disease %K Exome %K Female %K High-Throughput Nucleotide Sequencing %K Homozygote %K Humans %K Infant, Newborn %K Male %K Mutation, Missense %K Nuclear Proteins %K Vocal Cord Paralysis %X

Charcot-Marie-Tooth disease is a heterogeneous group of inherited distal symmetric polyneuropathies associated with mutations in genes encoding components essential for normal functioning of the Schwann cell and axon. TRIM2, encoding a ligase that ubiquitinates the neurofilament light chain, was recently associated with early-onset neuropathy in a single patient. We report a TRIM2 homozygous missense mutation (c.2000A>C; p.D667A) in a patient with peripheral neuropathy and bilateral vocal cord paralysis, allowing for further delineation of the associated phenotypic spectrum.

%B Hum Genet %V 134 %P 671-3 %8 2015 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/25893792?dopt=Abstract %R 10.1007/s00439-015-1548-3 %0 Journal Article %J Neuron %D 2015 %T Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. %A Karaca, Ender %A Harel, Tamar %A Pehlivan, Davut %A Jhangiani, Shalini N %A Gambin, Tomasz %A Coban Akdemir, Zeynep %A Gonzaga-Jauregui, Claudia %A Erdin, Serkan %A Bayram, Yavuz %A Campbell, Ian M %A Hunter, Jill V %A Atik, Mehmed M %A Van Esch, Hilde %A Yuan, Bo %A Wiszniewski, Wojciech %A Isikay, Sedat %A Yesil, Gozde %A Yuregir, Ozge O %A Tug Bozdogan, Sevcan %A Aslan, Huseyin %A Aydin, Hatip %A Tos, Tulay %A Aksoy, Ayse %A De Vivo, Darryl C %A Jain, Preti %A Geckinli, B Bilge %A Sezer, Ozlem %A Gul, Davut %A Durmaz, Burak %A Cogulu, Ozgur %A Ozkinay, Ferda %A Topcu, Vehap %A Candan, Sukru %A Cebi, Alper Han %A Ikbal, Mevlit %A Yilmaz Gulec, Elif %A Gezdirici, Alper %A Koparir, Erkan %A Ekici, Fatma %A Coskun, Salih %A Cicek, Salih %A Karaer, Kadri %A Koparir, Asuman %A Duz, Mehmet Bugrahan %A Kirat, Emre %A Fenercioglu, Elif %A Ulucan, Hakan %A Seven, Mehmet %A Guran, Tulay %A Elcioglu, Nursel %A Yildirim, Mahmut Selman %A Aktas, Dilek %A Alikaşifoğlu, Mehmet %A Ture, Mehmet %A Yakut, Tahsin %A Overton, John D %A Yuksel, Adnan %A Ozen, Mustafa %A Muzny, Donna M %A Adams, David R %A Boerwinkle, Eric %A Chung, Wendy K %A Gibbs, Richard A %A Lupski, James R %K Brain %K Cohort Studies %K Databases, Genetic %K Female %K Gene Regulatory Networks %K Genetic Association Studies %K Genetic Variation %K Humans %K Male %K Mendelian Randomization Analysis %K Nervous System Diseases %K Pedigree %X

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.

%B Neuron %V 88 %P 499-513 %8 2015 Nov 04 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/26539891?dopt=Abstract %R 10.1016/j.neuron.2015.09.048