TY - JOUR
T1 - Clinical delineation, sex differences, and genotype–phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2
AU - Faundes, Víctor
AU - Goh, Stephanie
AU - Akilapa, Rhoda
AU - Bezuidenhout, Heidre
AU - Bjornsson, Hans T.
AU - Bradley, Lisa
AU - Brady, Angela F.
AU - Brischoux-Boucher, Elise
AU - Brunner, Han
AU - Bulk, Saskia
AU - Canham, Natalie
AU - Cody, Declan
AU - Dentici, Maria Lisa
AU - Digilio, Maria Cristina
AU - Elmslie, Frances
AU - Fry, Andrew E.
AU - Gill, Harinder
AU - Hurst, Jane
AU - Johnson, Diana
AU - Julia, Sophie
AU - Lachlan, Katherine
AU - Lebel, Robert Roger
AU - Byler, Melissa
AU - Gershon, Eric
AU - Lemire, Edmond
AU - Gnazzo, Maria
AU - Lepri, Francesca Romana
AU - Marchese, Antonia
AU - McEntagart, Meriel
AU - McGaughran, Julie
AU - Mizuno, Seiji
AU - Okamoto, Nobuhiko
AU - Rieubland, Claudine
AU - Rodgers, Jonathan
AU - Sasaki, Erina
AU - Scalais, Emmanuel
AU - Scurr, Ingrid
AU - Suri, Mohnish
AU - van der Burgt, Ineke
AU - Matsumoto, Naomichi
AU - Miyake, Noriko
AU - Benoit, Valérie
AU - Lederer, Damien
AU - Banka, Siddharth
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/7
Y1 - 2021/7
N2 - Purpose: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood. Methods: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed. Results: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID. Conclusion: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.
AB - Purpose: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood. Methods: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed. Results: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID. Conclusion: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.
UR - http://www.scopus.com/inward/record.url?scp=85102053755&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102053755&partnerID=8YFLogxK
U2 - 10.1038/s41436-021-01119-8
DO - 10.1038/s41436-021-01119-8
M3 - Article
C2 - 33674768
AN - SCOPUS:85102053755
SN - 1098-3600
VL - 23
SP - 1202
EP - 1210
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 7
ER -