@article {680, title = {Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease.}, journal = {J Clin Endocrinol Metab}, volume = {104}, year = {2019}, month = {2019 Aug 01}, pages = {3049-3067}, 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.

}, issn = {1945-7197}, doi = {10.1210/jc.2019-00248}, author = {Jolly, Angad and Bayram, Yavuz and Turan, Serap and Aycan, Zehra and Tos, Tulay and Abali, Zehra Yavas and Hacihamdioglu, Bulent and Coban Akdemir, Zeynep Hande and Hijazi, Hadia and Bas, Serpil and Atay, Zeynep and Guran, Tulay and Abali, Saygin and Bas, Firdevs and Darendeliler, Feyza and Colombo, Roberto and Barakat, Tahsin Stefan and Rinne, Tuula and White, Janson J and Yesil, G{\"o}zde and Gezdirici, Alper and Gulec, Elif Yilmaz and Karaca, Ender and Pehlivan, Davut and Jhangiani, Shalini N and Muzny, Donna M and Poyrazoglu, Sukran and Bereket, Abdullah and Gibbs, Richard A and Posey, Jennifer E and Lupski, James R} } @article {620, title = {Mutations in the mitochondrial ribosomal protein MRPS22 lead to primary ovarian insufficiency.}, journal = {Hum Mol Genet}, volume = {27}, year = {2018}, month = {2018 06 01}, pages = {1913-1926}, abstract = {

Primary ovarian insufficiency (POI) is characterized by amenorrhea and loss or dysfunction of ovarian follicles prior to the age of 40. POI has been associated with autosomal recessive mutations in genes involving hormonal signaling and folliculogenesis, however, the genetic etiology of POI most often remains unknown. Here we report MRPS22 homozygous missense variants c.404G>A (p.R135Q) and c.605G>A (p.R202H) identified in four females from two independent consanguineous families as a novel genetic cause of POI in adolescents. Both missense mutations identified in MRPS22 are rare, occurred in highly evolutionarily conserved residues, and are predicted to be deleterious to protein function. In contrast to prior reports of mutations in MRPS22 associated with severe mitochondrial disease, the POI phenotype is far less severe. Consistent with this genotype-phenotype correlation, mitochondrial defects in oxidative phosphorylation or rRNA levels were not detected in fibroblasts derived from the POI patients, suggesting a non-bioenergetic or tissue-specific mitochondrial defect. Furthermore, we demonstrate in a Drosophila model that mRpS22 deficiency specifically in somatic cells of the ovary had no effect on fertility, whereas flies with mRpS22 deficiency specifically in germ cells were infertile and agametic, demonstrating a cell autonomous requirement for mRpS22 in germ cell development. These findings collectively identify that MRPS22, a component of the small mitochondrial ribosome subunit, is critical for ovarian development and may therefore provide insight into the pathophysiology and treatment of ovarian dysfunction.

}, keywords = {Adolescent, Adult, Amenorrhea, Animals, Disease Models, Animal, Drosophila, Drosophila Proteins, Female, Fertility, Homozygote, Humans, Menopause, Premature, Mitochondrial Proteins, Mutation, Missense, Ovarian Follicle, Primary Ovarian Insufficiency, Ribosomal Proteins, Young Adult}, issn = {1460-2083}, doi = {10.1093/hmg/ddy098}, author = {Chen, Anlu and Tiosano, Dov and Guran, Tulay and Baris, Hagit N and Bayram, Yavuz and Mory, Adi and Shapiro-Kulnane, Laura and Hodges, Craig A and Akdemir, Zeynep C and Turan, Serap and Jhangiani, Shalini N and van den Akker, Focco and Hoppel, Charles L and Salz, Helen K and Lupski, James R and Buchner, David A} } @article {121, title = {Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.}, journal = {Neuron}, volume = {88}, year = {2015}, month = {2015 Nov 04}, pages = {499-513}, abstract = {

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.

}, keywords = {Brain, Cohort Studies, Databases, Genetic, Female, Gene Regulatory Networks, Genetic Association Studies, Genetic Variation, Humans, Male, Mendelian Randomization Analysis, Nervous System Diseases, Pedigree}, issn = {1097-4199}, doi = {10.1016/j.neuron.2015.09.048}, author = {Karaca, Ender and Harel, Tamar and Pehlivan, Davut and Jhangiani, Shalini N and Gambin, Tomasz and Coban Akdemir, Zeynep and Gonzaga-Jauregui, Claudia and Erdin, Serkan and Bayram, Yavuz and Campbell, Ian M and Hunter, Jill V and Atik, Mehmed M and Van Esch, Hilde and Yuan, Bo and Wiszniewski, Wojciech and Isikay, Sedat and Yesil, G{\"o}zde and Yuregir, Ozge O and Tug Bozdogan, Sevcan and Aslan, Huseyin and Aydin, Hatip and Tos, Tulay and Aksoy, Ayse and De Vivo, Darryl C and Jain, Preti and Geckinli, B Bilge and Sezer, Ozlem and Gul, Davut and Durmaz, Burak and Cogulu, Ozgur and Ozkinay, Ferda and Topcu, Vehap and Candan, Sukru and Cebi, Alper Han and Ikbal, Mevlit and Yilmaz Gulec, Elif and Gezdirici, Alper and Koparir, Erkan and Ekici, Fatma and Coskun, Salih and Cicek, Salih and Karaer, Kadri and Koparir, Asuman and Duz, Mehmet Bugrahan and Kirat, Emre and Fenercioglu, Elif and Ulucan, Hakan and Seven, Mehmet and Guran, Tulay and Elcioglu, Nursel and Yildirim, Mahmut Selman and Aktas, Dilek and Alika{\c s}ifo{\u g}lu, Mehmet and Ture, Mehmet and Yakut, Tahsin and Overton, John D and Yuksel, Adnan and Ozen, Mustafa and Muzny, Donna M and Adams, David R and Boerwinkle, Eric and Chung, Wendy K and Gibbs, Richard A and Lupski, James R} } @article {186, title = {Homozygous loss-of-function mutations in SOHLH1 in patients with nonsyndromic hypergonadotropic hypogonadism.}, journal = {J Clin Endocrinol Metab}, volume = {100}, year = {2015}, month = {2015 May}, pages = {E808-14}, abstract = {

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.

}, keywords = {Adolescent, Basic Helix-Loop-Helix Transcription Factors, Child, Exome, Female, Homozygote, Humans, Hypogonadism, Mutation}, issn = {1945-7197}, doi = {10.1210/jc.2015-1150}, author = {Bayram, Yavuz and Gulsuner, Suleyman and Guran, Tulay and Abaci, Ayhan and Yesil, G{\"o}zde and Gulsuner, Hilal Unal and Atay, Zeynep and Pierce, Sarah B and Gambin, Tomasz and Lee, Ming and Turan, Serap and Bober, Ece and Atik, Mehmed M and Walsh, Tom and Karaca, Ender and Pehlivan, Davut and Jhangiani, Shalini N and Muzny, Donna and Bereket, Abdullah and Buyukgebiz, Atilla and Boerwinkle, Eric and Gibbs, Richard A and King, Mary-Claire and Lupski, James R} }