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 - Funding Information:
We thank Frederic Tran‐Mau‐Them (Inserm UMR1231 GAD, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France) for the RNA splicing experiments performed for individual 5. Jette Bune Rasmussen (Department of Clinical Genetics, Copenhagen University Hospital—Rigshospitalet) is acknowledged for her graphical support. Kathleen Pope (MD, Division of Genetics, Nemours Children's Hospital, USA) is acknowledged for the clinical information of individual 6 and Eléonore Viora‐Dupont (Medical student, Centre de Génétique Clinique, CHU de Dijon) for the further clinical information of individuals 5 and 11. Part of this work has been generated within the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERNITHACA) [EU Framework Partnership Agreement ID: 3HP‐HP‐FPA ERN‐01‐2016/739516]. This study was supported by the National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI)'s grant (UM1 HG006542), the Rashid Family Fund, the Centro Portugal Regional Operational Programme (CENTRO 2020) through the European Regional Development Fund (ERDF), the Spanish Ministry of Science/State Research Agency projects (RTC‐2017‐6494‐1, RTI2018‐094434‐B‐I00, and DTS20‐00024), the European Commission JPIAMR projects CONNECT and AEPIC, the Raregenomics network through the Consejería de Educación de la C. de Madrid (S2017/BMD‐3721), the European Social Fund to María Palomares‐Bralo, ISCIII, Ministerio de Ciencia e Innovación (PI19/01681), the National Human Genome Research Institute (NHGRI) (K08 HG008986), the National Center for Advancing Translational Sciences, National Institutes of Health (UL1TR001873), the Undiagnosed Diseases Network, the NIH Common Fund through the Office of Strategic Coordination/Office of the NIH Director (U01HG007709), and the SFARI and JPB Foundation.
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
VL - 43
SP - 266
EP - 282
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 2
ER -