Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants.

TitleFurther delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants.
Publication TypeJournal Article
Year of Publication2020
AuthorsZhang, LXin, Lemire, G, Gonzaga-Jauregui, C, Molidperee, S, Galaz-Montoya, C, Liu, DS, Verloes, A, Shillington, AG, Izumi, K, Ritter, AL, Keena, B, Zackai, E, Li, D, Bhoj, E, Tarpinian, JM, Bedoukian, E, Kukolich, MK, A Innes, M, Ediae, GU, Sawyer, SL, Nair, KMohandas, Soumya, PChottil, Subbaraman, KR, Probst, FJ, Bassetti, JA, Sutton, RV, Gibbs, RA, Brown, C, Boone, PM, Holm, IA, Tartaglia, M, Ferrero, GBattista, Niceta, M, Dentici, MLisa, Radio, FClementina, Keren, B, Wells, CF, Coubes, C, Laquerrière, A, Aziza, J, Dubucs, C, Nampoothiri, S, Mowat, D, Patel, MS, Bracho, A, Cammarata-Scalisi, F, Gezdirici, A, Fernández-Jaén, A, Hauser, N, Zarate, YA, Bosanko, KA, Dieterich, K, Carey, JC, Chong, JX, Nickerson, DA, Bamshad, MJ, Lee, BH, Yang, X-J, Lupski, JR, Campeau, PM
JournalGenet Med
Date Published2020 08
KeywordsBlepharophimosis, Exons, Histone Acetyltransferases, Humans, Intellectual Disability, Mutation

PURPOSE: Genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized.

METHODS: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum.

RESULTS: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent.

CONCLUSION: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.

Alternate JournalGenet Med
PubMed ID32424177
PubMed Central IDPMC7737399
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
/ / CIHR / Canada
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States
T32 GM007748 / GM / NIGMS NIH HHS / United States