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The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder
Author(s) -
Kumble Smitha,
Levy Amanda M.,
Punetha Jaya,
Gao Hua,
Ah Mew Nicholas,
AnyaneYeboa Kwame,
Benke Paul J.,
Berger Sara M.,
Bjerglund Lise,
CamposXavier Belinda,
Ciliberto Michael,
Cohen Julie S.,
Comi Anne M.,
Curry Cynthia,
Damaj Lena,
DenomméPichon AnneSophie,
Emrick Lisa,
Faivre Laurence,
Fasano Mary Beth,
Fiévet Alice,
Finkel Richard S.,
GarcíaMiñaúr Sixto,
Gerard Amanda,
GomezPuertas Paulino,
Guillen Sacoto Maria J.,
Hoffman Trevor L.,
Howard Lillian,
Iglesias Alejandro D.,
Izumi Kosuke,
Larson Austin,
Leiber Anja,
Lozano Reymundo,
MarcosAlcalde Iñigo,
Mintz Cassie S.,
Mullegama Sureni V.,
Møller Rikke S.,
Odent Sylvie,
Oppermann Henry,
Ostergaard Elsebet,
PacioMíguez Marta,
PalomaresBralo Maria,
Parikh Sumit,
Paulson Anna M.,
Platzer Konrad,
Posey Jennifer E.,
Potocki Lorraine,
RevahPoliti Anya,
Rio Marlene,
Ritter Alyssa L.,
Robinson Scott,
Rosenfeld Jill A.,
SantosSimarro Fernando,
Sousa Sérgio B.,
Wéber Mathys,
Xie Yili,
Chung Wendy K.,
Brown Natasha J.,
Tümer Zeynep
Publication year - 2022
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24308
Subject(s) - hypotonia , autism spectrum disorder , biology , intellectual disability , missense mutation , neurodevelopmental disorder , short stature , genetics , dup , global developmental delay , phenotype , muscle hypotonia , autism , endocrinology , psychology , gene duplication , psychiatry , gene
De novo variants in QRICH1 (Glutamine‐rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals ( n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.