De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females.
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
22
07
2020
accepted:
15
10
2020
pubmed:
28
11
2020
medline:
4
6
2021
entrez:
27
11
2020
Statut:
ppublish
Résumé
Hardikar syndrome (MIM 612726) is a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, but with preserved cognition. Only four patients have been reported previously, and none had a molecular diagnosis. Our objective was to identify the genetic basis of Hardikar syndrome (HS) and expand the phenotypic spectrum of this disorder. We performed exome sequencing on two previously reported and five unpublished female patients with a clinical diagnosis of HS. X-chromosome inactivation (XCI) studies were also performed. We report clinical features of HS with previously undescribed phenotypes, including a fatal unprovoked intracranial hemorrhage at age 21. We additionally report the discovery of de novo pathogenic nonsense and frameshift variants in MED12 in these seven individuals and evidence of extremely skewed XCI in all patients with informative testing. Pathogenic missense variants in the X-chromosome gene MED12 have previously been associated with Opitz-Kaveggia syndrome, Lujan syndrome, Ohdo syndrome, and nonsyndromic intellectual disability, primarily in males. We propose a fifth, female-specific phenotype for MED12, and suggest that nonsense and frameshift loss-of-function MED12 variants in females cause HS. This expands the MED12-associated phenotype in females beyond intellectual disability.
Identifiants
pubmed: 33244166
doi: 10.1038/s41436-020-01031-7
pii: S1098-3600(21)02450-3
doi:
Substances chimiques
MED12 protein, human
0
Mediator Complex
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
637-644Références
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