TY - JOUR
T1 - The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder
AU - Undiagnosed Diseases Network
AU - Kumble, Smitha
AU - Levy, Amanda M.
AU - Punetha, Jaya
AU - Gao, Hua
AU - Ah Mew, Nicholas
AU - Anyane-Yeboa, Kwame
AU - Benke, Paul J.
AU - Berger, Sara M.
AU - Bjerglund, Lise
AU - Campos-Xavier, Belinda
AU - Ciliberto, Michael
AU - Cohen, Julie S.
AU - Comi, Anne M.
AU - Curry, Cynthia
AU - Damaj, Lena
AU - Denommé-Pichon, Anne Sophie
AU - Emrick, Lisa
AU - Faivre, Laurence
AU - Fasano, Mary Beth
AU - Fiévet, Alice
AU - Finkel, Richard S.
AU - García-Miñaúr, Sixto
AU - Gerard, Amanda
AU - Gomez-Puertas, Paulino
AU - Guillen Sacoto, Maria J.
AU - Hoffman, Trevor L.
AU - Howard, Lillian
AU - Iglesias, Alejandro D.
AU - Izumi, Kosuke
AU - Larson, Austin
AU - Leiber, Anja
AU - Lozano, Reymundo
AU - Marcos-Alcalde, Iñigo
AU - Mintz, Cassie S.
AU - Mullegama, Sureni V.
AU - Møller, Rikke S.
AU - Odent, Sylvie
AU - Oppermann, Henry
AU - Ostergaard, Elsebet
AU - Pacio-Míguez, Marta
AU - Palomares-Bralo, Maria
AU - Parikh, Sumit
AU - Paulson, Anna M.
AU - Platzer, Konrad
AU - Posey, Jennifer E.
AU - Dasari, Surendra
AU - Lanpher, Brendan C.
AU - Lanza, Ian R.
AU - Morava, Eva
AU - Oglesbee, Devin
N1 - Publisher Copyright:
© 2021 Wiley Periodicals LLC.
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
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U2 - 10.1002/humu.24308
DO - 10.1002/humu.24308
M3 - Article
C2 - 34859529
AN - SCOPUS:85120961215
SN - 1059-7794
VL - 43
SP - 266
EP - 282
JO - Human mutation
JF - Human mutation
IS - 2
ER -