Browsing by Author "Masser-Frye, Diane"

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    Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations
    (Elsevier, 2020-01-12) Hughes, Joel J.; Alkhunaizi, Ebba; Kruszka, Paul; Pyle, Louise C.; Grange, Dorothy K.; Berger, Seth I.; Payne, Katelyn K.; Masser-Frye, Diane; Hu, Tommy; Christie, Michelle R.; Clegg, Nancy J.; Everson, Joshua L.; Martinez, Ariel F.; Walsh, Laurence E.; Bedoukian, Emma; Jones, Marilyn C.; Harris, Catharine Jean; Riedhammer, Korbinian M.; Choukair, Daniela; Fechner, Patricia Y.; Rutter, Meilan M.; Hufnagel, Sophia B.; Roifman, Maian; Kletter, Gad B.; Delot, Emmanuele; Vilain, Eric; Lipinski, Robert J.; Vezina, Chad M.; Muenke, Maximilian; Chitayat, David; Pediatrics, School of Medicine
    In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.
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    The impact of clinical genome sequencing in a global population with suspected rare genetic disease
    (Elsevier, 2024) Thorpe, Erin; Williams, Taylor; Shaw, Chad; Chekalin, Evgenii; Ortega, Julia; Robinson, Keisha; Button, Jason; Jones, Marilyn C.; Del Campo, Miguel; Basel, Donald; McCarrier, Julie; Davis Keppen, Laura; Royer, Erin; Foster-Bonds, Romina; Duenas-Roque, Milagros M.; Urraca, Nora; Bosfield, Kerri; Brown, Chester W.; Lydigsen, Holly; Mroczkowski, Henry J.; Ward, Jewell; Sirchia, Fabio; Giorgio, Elisa; Vaux, Keith; Peña Salguero, Hildegard; Lumaka, Aimé; Mubungu, Gerrye; Makay, Prince; Ngole, Mamy; Tshilobo Lukusa, Prosper; Vanderver, Adeline; Muirhead, Kayla; Sherbini, Omar; Lah, Melissa D.; Anderson, Katelynn; Bazalar-Montoya, Jeny; Rodriguez, Richard S.; Cornejo-Olivas, Mario; Milla-Neyra, Karina; Shinaw, Marwan; Magoulas, Pilar; Henry, Duncan; Gibson, Kate; Wiaf, Samuel; Jayakar, Parul; Salyakina, Daria; Masser-Frye, Diane; Serize, Arturo; Perez, Jorge E.; Taylor, Alan; Shenbagam, Shruti; Tayoun, Ahmad Abou; Malhotra, Alka; Bennett, Maren; Rajan, Vani; Avecilla, James; Warren, Andrew; Arseneault, Max; Kalista, Tasha; Crawford, Ali; Ajay, Subramanian S.; Perry, Denise L.; Belmont, John; Taft, Ryan J.; Medicine, School of Medicine
    There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.