%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 Ann Neurol %D 2021 %T MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia. %A Meng, Linyan %A Isohanni, Pirjo %A Shao, Yunru %A Graham, Brett H %A Hickey, Scott E %A Brooks, Stephanie %A Suomalainen, Anu %A Joset, Pascal %A Steindl, Katharina %A Rauch, Anita %A Hackenberg, Annette %A High, Frances A %A Armstrong-Javors, Amy %A Mencacci, Niccolò E %A Gonzàlez-Latapi, Paulina %A Kamel, Walaa A %A Al-Hashel, Jasem Y %A Bustos, Bernabé I %A Hernandez, Alejandro V %A Krainc, Dimitri %A Lubbe, Steven J %A Van Esch, Hilde %A De Luca, Chiara %A Ballon, Katleen %A Ravelli, Claudia %A Burglen, Lydie %A Qebibo, Leila %A Calame, Daniel G %A Mitani, Tadahiro %A Marafi, Dana %A Pehlivan, Davut %A Saadi, Nebal W %A Sahin, Yavuz %A Maroofian, Reza %A Efthymiou, Stephanie %A Houlden, Henry %A Maqbool, Shazia %A Rahman, Fatima %A Gu, Shen %A Posey, Jennifer E %A James R Lupski %A Hunter, Jill V %A Wangler, Michael F %A Carroll, Christopher J %A Yang, Yaping %K Adolescent %K Adult %K Amino Acid Sequence %K Cataract %K Cerebellum %K Child %K Child, Preschool %K Developmental Disabilities %K Dystonia %K Epilepsy %K Exome Sequencing %K Genetic Variation %K Humans %K Infant %K Mediator Complex %K Nervous System Malformations %K Phenotype %X

The Mediator multiprotein complex functions as a regulator of RNA polymerase II-catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021;89:828-833.

%B Ann Neurol %V 89 %P 828-833 %8 2021 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33443317?dopt=Abstract %R 10.1002/ana.26019 %0 Journal Article %J Eur J Hum Genet %D 2020 %T Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide. %A Gonzaga-Jauregui, Claudia %A Yesil, Gozde %A Nistala, Harikiran %A Gezdirici, Alper %A Bayram, Yavuz %A Nannuru, Kalyan C %A Pehlivan, Davut %A Bo Yuan %A Jimenez, Johanna %A Sahin, Yavuz %A Paine, Ingrid S %A Akdemir, Zeynep Coban %A Rajamani, Saathyaki %A Staples, Jeffrey %A Dronzek, John %A Howell, Kristen %A Fatih, Jawid M %A Smaldone, Silvia %A Schlesinger, Alan E %A Ramírez, Norman %A Cornier, Alberto S %A Kelly, Melissa A %A Haber, Robert %A Chim, Shek Man %A Nieman, Kristy %A Wu, Nan %A Walls, Johnathon %A Poueymirou, William %A Siao, Chia-Jen %A Sutton, V Reid %A Williams, Marc S %A Posey, Jennifer E %A Richard A Gibbs %A Carlo, Simon %A Tegay, David H %A Economides, Aris N %A James R Lupski %K Abnormalities, Multiple %K Adolescent %K Animals %K Bone Development %K Child %K Child, Preschool %K Consanguinity %K Extracellular Matrix %K Female %K Fibrillar Collagens %K Founder Effect %K Gene Frequency %K Hip Dislocation %K Homozygote %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mutation %K Pedigree %K Scoliosis %K Syndrome %X

Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

%B Eur J Hum Genet %V 28 %P 1243-1264 %8 2020 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/32376988?dopt=Abstract %R 10.1038/s41431-020-0632-x %0 Journal Article %J Am J Hum Genet %D 2019 %T The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance. %A Pehlivan, Davut %A Bayram, Yavuz %A Gunes, Nilay %A Coban Akdemir, Zeynep %A Shukla, Anju %A Bierhals, Tatjana %A Tabakci, Burcu %A Sahin, Yavuz %A Gezdirici, Alper %A Fatih, Jawid M %A Gulec, Elif Yilmaz %A Yesil, Gozde %A Punetha, Jaya %A Ocak, Zeynep %A Grochowski, Christopher M %A Karaca, Ender %A Albayrak, Hatice Mutlu %A Radhakrishnan, Periyasamy %A Erdem, Haktan Bagis %A Sahin, Ibrahim %A Yildirim, Timur %A Bayhan, Ilhan A %A Bursali, Aysegul %A Elmas, Muhsin %A Yuksel, Zafer %A Ozdemir, Ozturk %A Silan, Fatma %A Yildiz, Onur %A Yesilbas, Osman %A Isikay, Sedat %A Balta, Burhan %A Gu, Shen %A Jhangiani, Shalini N %A Harshavardhan Doddapaneni %A Jianhong Hu %A Donna M Muzny %A Eric Boerwinkle %A Richard A Gibbs %A Tsiakas, Konstantinos %A Hempel, Maja %A Girisha, Katta Mohan %A Gul, Davut %A Posey, Jennifer E %A Elcioglu, Nursel H %A Tuysuz, Beyhan %A James R Lupski %K Adolescent %K Adult %K Arthrogryposis %K Child %K Child, Preschool %K Cohort Studies %K Connectin %K DNA Copy Number Variations %K Exome Sequencing %K Female %K Genetic Markers %K Genomics %K Gestational Age %K Humans %K Infant %K Infant, Newborn %K Male %K Mosaicism %K Multifactorial Inheritance %K Mutation %K Pedigree %K Ryanodine Receptor Calcium Release Channel %K Vesicular Transport Proteins %K Young Adult %X

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.

%B Am J Hum Genet %V 105 %P 132-150 %8 2019 Jul 03 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31230720?dopt=Abstract %R 10.1016/j.ajhg.2019.05.015