De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females

TY - JOUR

T1 - De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females

AU - Li, Dong

AU - Strong, Alanna

AU - Shen, Kaitlyn M

AU - Cassiman, David

AU - Van Dyck, Maria

AU - Linhares, Natalia Duarte

AU - Valadares, Eugenia Ribeiro

AU - Wang, Tiancheng

AU - Pena, Sergio D J

AU - Jaeken, Jaak

AU - Vergano, Samantha

AU - Zackai, Elaine

AU - Hing, Anne

AU - Chow, Penny

AU - Ganguly, Arupa

AU - Scholz, Tasja

AU - Bierhals, Tatjana

AU - Deindl, Philipp

AU - Hakonarson, Hakon

AU - Bhoj, Elizabeth

PY - 2021/4

Y1 - 2021/4

N2 - PURPOSE: 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the phenotypic spectrum of this disorder.METHODS: We performed exome sequencing on two previously reported and five unpublished female patients with a clinical diagnosis of HS.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.RESULTS: 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.CONCLUSION: 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.

AB - PURPOSE: 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.METHODS: 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.RESULTS: 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.CONCLUSION: 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.

U2 - 10.1038/s41436-020-01031-7

DO - 10.1038/s41436-020-01031-7

M3 - SCORING: Journal article

C2 - 33244166

VL - 23

SP - 637

EP - 644

JO - GENET MED

JF - GENET MED

SN - 1098-3600

IS - 4

ER -