The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder

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  • Smitha Kumble
  • Undiagnosed Diseases Network

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.

OriginalsprogEngelsk
TidsskriftHuman Mutation
Vol/bind43
Udgave nummer2
Sider (fra-til) 266-282
ISSN1059-7794
DOI
StatusUdgivet - 2022

Bibliografisk note

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.

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