The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder

Smitha Kumble (1) , Amanda Levy (2) , Jaya Punetha (3, 4) , Hua Gao , Nicholas Ah Mew , Kwame Anyane-Yeboa , Paul Benke , Sara Berger , Lise Bjerglund , Belinda Campos-Xavier , Michael Ciliberto , Julie Cohen , Anne Comi , Cynthia Curry , Lena Damaj (5) , Anne-Sophie Denommé-Pichon (6, 7, 8) , Lisa Emrick (3) , Laurence Faivre (9, 7, 8) , Mary Beth Fasano , Alice Fiévet (10, 11) , Richard Finkel , Sixto García-Miñaúr , Amanda Gerard , Paulino Gomez-Puertas , Maria Guillen Sacoto , Trevor Hoffman , Lillian Howard , Alejandro Iglesias , Kosuke Izumi , Austin Larson , Anja Leiber , Reymundo Lozano , Iñigo Marcos-Alcalde , Cassie Mintz , Sureni Mullegama , Rikke Møller , Sylvie Odent (5, 12, 13) , Henry Oppermann , Elsebet Ostergaard , Marta Pacio-Míguez , Maria Palomares-Bralo , Sumit Parikh , Anna Paulson , Konrad Platzer , Jennifer Posey , Lorraine Potocki , Anya Revah-Politi , Marlene Rio , Alyssa Ritter , Scott Robinson , Jill Rosenfeld , Fernando Santos-Simarro , Kwame Anyane‐yeboa , Belinda Campos‐xavier , Anne‐sophie Denommé‐pichon , Sixto García‐miñaúr , Paulino Gomez‐puertas , Iñigo Marcos‐alcalde , Marta Pacio‐míguez , Maria Palomares‐bralo , Anya Revah‐politi , Fernando Santos‐simarro (14) , Sérgio Sousa Sombra , Mathys Wéber (8) , Yili Xie (15) , Wendy K. Chung (16) , Natasha J Brown (1, 17) , Zeynep Tümer (2, 18)

1 MCRI - Murdoch Children's Research Institute
2 Copenhagen University Hospital
3 BCM - Baylor College of Medicine
4 MSSM - Icahn School of Medicine at Mount Sinai [New York]
5 CHU Pontchaillou [Rennes]
6 UBFC - Université Bourgogne Franche-Comté [COMUE]
7 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
8 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
9 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
10 IGR - Institut Gustave Roussy
11 Département de biologie et pathologie médicales [Gustave Roussy]
12 IGDR - Institut de Génétique et Développement de Rennes
13 Centre de référence Maladies Rares CLAD-Ouest [Rennes]
14 CIBER de Enfermedades Raras (CIBERER)
15 GeneDx [Gaithersburg, MD, USA]
16 CUIMC - Columbia University Irving Medical Center
17 University of Melbourne
18 UCPH - University of Copenhagen = Københavns Universitet

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.

Keywords: QRICH1; hypotonia; intellectual disability; short stature; variable expressivity; variant

Domains: Life Sciences [q-bio]

Smitha Kumble, Amanda Levy, Jaya Punetha, Hua Gao, Nicholas Ah Mew, et al.. The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder. Human Mutation, 2022, 43 (2), pp.266-282. ⟨10.1002/humu.24308⟩. ⟨hal-03519376⟩