Browsing by Author "Kleyner, Robert"

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    Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity
    (Wiley, 2019-10-23) Cheng, Hanyin; Capponi, Simona; Wakeling, Emma; Marchi, Elaine; Li, Quan; Zhao, Mengge; Weng, Chunhua; Piatek, Stefan G.; Ahlfors, Helena; Kleyner, Robert; Rope, Alan; Lumaka, Aimé; Lukusa, Prosper; Devriendt, Koenraad; Vermeesch, Joris; Posey, Jennifer E.; Palmer, Elizabeth E.; Murray, Lucinda; Leon, Eyby; Diaz, Jullianne; Worgan, Lisa; Mallawaarachchi, Amali; Vogt, Julie; de Munnik, Sonja A.; Dreyer, Lauren; Baynam, Gareth; Ewans, Lisa; Stark, Zornitza; Lunke, Sebastian; Gonçalves, Ana R.; Soares, Gabriela; Oliveira, Jorge; Fassi, Emily; Willing, Marcia; Waugh, Jeff L.; Faivre, Laurence; Riviere, Jean-Baptiste; Moutton, Sebastien; Mohammed, Shehla; Payne, Katelyn; Walsh, Laurence; Begtrup, Amber; Guillen Sacoto, Maria J.; Douglas, Ganka; Alexander, Nora; Buckley, Michael F.; Mark, Paul R.; Adès, Lesley C.; Sandaradura, Sarah A.; Lupski, James R.; Roscioli, Tony; Agrawal, Pankaj B.; Kline, Antonie D.; Wang, Kai; Timmers, T. Marc; Lyon, Gholson J.; Neurology, School of Medicine
    We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X.
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    Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15
    (Oxford University Press, 2019-05-01) Cheng, Hanyin; Gottlieb, Leah; Marchi, Elaine; Kleyner, Robert; Bhardwaj, Puja; Rope, Alan F.; Rosenheck, Sarah; Moutton, Sébastien; Philippe, Christophe; Eyaid, Wafaa; Alkuraya, Fowzan S.; Toribio, Janet; Mena, Rafael; Prada, Carlos E.; Stessman, Holly; Bernier, Raphael; Wermuth, Marieke; Kauffmann, Birgit; Blaumeiser, Bettina; Kooy, R Frank; Baralle, Diana; Mancini, Grazia M. S.; Conway, Simon J.; Xia, Fan; Chen, Zhao; Meng, Linyan; Mihajlovic, Ljubisa; Marmorstein, Ronen; Lyon, Gholson J.; Pediatrics, School of Medicine
    N-alpha-acetylation is one of the most common co-translational protein modifications in humans and is essential for normal cell function. NAA10 encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. The auxiliary and regulatory subunits of the NatA complex are NAA15 and Huntington-interacting protein (HYPK), respectively. Through a genotype-first approach with exome sequencing, we identified and phenotypically characterized 30 individuals from 30 unrelated families with 17 different de novo or inherited, dominantly acting missense variants in NAA10 or NAA15. Clinical features of affected individuals include variable levels of intellectual disability, delayed speech and motor milestones and autism spectrum disorder. Additionally, some subjects present with mild craniofacial dysmorphology, congenital cardiac anomalies and seizures. One of the individuals is an 11-year-old boy with a frameshift variant in exon 7 of NAA10, who presents most notably with microphthalmia, which confirms a prior finding with a single family with Lenz microphthalmia syndrome. Biochemical analyses of variants as part of the human NatA complex, as well as enzymatic analyses with and without the HYPK regulatory subunit, help to explain some of the phenotypic differences seen among the different variants.
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    Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15
    (Oxford University Press, 2020-03-27) Cheng, Hanyin; Gottlieb, Leah; Marchi, Elaine; Kleyner, Robert; Bhardwaj, Puja; Rope, Alan F.; Rosenheck, Sarah; Moutton, Sébastien; Philippe, Christophe; Eyaid, Wafaa; Alkuraya, Fowzan S.; Toribio, Janet; Mena, Rafael; Prada, Carlos E.; Stessman, Holly; Bernier, Raphael; Wermuth, Marieke; Kauffmann, Birgit; Blaumeiser, Bettina; Kooy, R. Frank; Baralle, Diana; Mancini, Grazia M. S.; Conway, Simon J.; Xia, Fan; Chen, Zhao; Meng, Linyan; Mihajlovic, Ljubisa; Marmorstein, Ronen; Lyon, Gholson J.; Medicine, School of Medicine
    In the original version of this article, Ezzat El-Akkad’s name was misspelled in the acknowledgements section; this has now been corrected. The authors apologize for this error.