The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder

Smitha Kumble¹, Amanda M Levy², Jaya Punetha^{3

4}, Hua Gao⁵, Nicholas Ah Mew⁶, Kwame Anyane-Yeboa⁷, Paul J Benke⁸, Sara M Berger⁷, Lise Bjerglund⁹, Belinda Campos-Xavier^{10

11}, Michael Ciliberto¹², Julie S Cohen^{13

14}, Anne M Comi^{13

15}, Cynthia Curry¹⁶, Lena Damaj¹⁷, Anne-Sophie Denommé-Pichon^{18

19}, Lisa Emrick^{3

20}, Laurence Faivre^{21

22}, Mary Beth Fasano²³, Alice Fiévet^{24

25}, Richard S Finkel^{26

27}, Sixto García-Miñaúr^{28

29}, Amanda Gerard^{3

30}, Paulino Gomez-Puertas³¹, Maria J Guillen Sacoto³², Trevor L Hoffman³³, Lillian Howard¹², Alejandro D Iglesias³⁴, Kosuke Izumi³⁵, Austin Larson³⁶, Anja Leiber³⁷, Reymundo Lozano⁴, Iñigo Marcos-Alcalde^{31

38}, Cassie S Mintz⁴, Sureni V Mullegama³², Rikke S Møller^{39

40}, Sylvie Odent⁴¹, Henry Oppermann⁴², Elsebet Ostergaard^{43

44}, Marta Pacio-Míguez²⁸, Maria Palomares-Bralo^{28

29}, Sumit Parikh⁴⁵, Anna M Paulson¹², Konrad Platzer⁴², Jennifer E Posey³, Lorraine Potocki^{3

30}, Anya Revah-Politi^{46

47}, Marlene Rio⁴⁸, Alyssa L Ritter³⁵, Scott Robinson⁷, Jill A Rosenfeld^{3

49}, Fernando Santos-Simarro^{28

29}, Sérgio B Sousa^{10

50}; Undiagnosed Diseases Network; Mathys Wéber²¹, Yili Xie³², Wendy K Chung⁷, Natasha J Brown^{1

51}, Zeynep Tümer^{2

44}

Affiliations

¹ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.
² Department of Clinical Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
³ Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
⁵ Department of Review Analysis, GeneDx LLC, Maryland, USA.
⁶ Rare Disease Institute, Children's National Hospital, Washington, District of Columbia, USA.
⁷ Department of Pediatrics, Columbia University Irving Medical Center, New York City, New York, USA.
⁸ Division of Genetics, Joe DiMaggio Children's Hospital, Hollywood, Florida, USA.
⁹ Department of Pediatrics, University Hospital Hvidovre, Hvidovre, Denmark.
¹⁰ Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
¹¹ Division of Genetic Medicine, Lausanne University Hospital and University of Lausanne (CHUV), Lausanne, Switzerland.
¹² Stead Family Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.
¹³ Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, Maryland, USA.
¹⁴ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁵ Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁶ Deptartment of Pediatrics, Genetic Medicine, UCSF/Fresno, Fresno, California, USA.
¹⁷ Service de pédiatrie et de génétique clinique, CHU Rennes, Rennes, France.
¹⁸ INSERM UMR1231 Equipe GAD, Université de Bourgogne, Dijon, France.
¹⁹ Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
²⁰ Division of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
²¹ Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France.
²² Inserm UMR1231 GAD, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.
²³ Internal Medicine & Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
²⁴ Laboratoire de biologie médicale multisites Seqoia-FMG2025, Paris, France.
²⁵ Service Génétique des Tumeurs, Gustave Roussy, Villejuif, France.
²⁶ Nemours Children's Hospital, Orlando, Florida, USA.
²⁷ Center for Experimental Neurotherapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
²⁸ Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Idipaz, Madrid, Spain.
²⁹ Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, U753), Instituto Carlos III, Madrid, Spain.
³⁰ Texas Children's Hospital, Houston, Texas, USA.
³¹ Molecular Modelling Group, Severo Ochoa Molecular Biology Centre (CBMSO, CSIC-UAM), Madrid, Spain.
³² Clinical Genomics Program, GeneDx, Maryland, USA.
³³ Regional Department of Genetics, Southern California Kaiser Permanente Medical Group, Pasadena, California, USA.
³⁴ Division of Clinical Genetics, Columbia University Irving Medical Center, New York City, New York, USA.
³⁵ Divison of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³⁶ Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
³⁷ Department of Neuropediatrics, Childrens Hospital of Eastern Switzerland St. Gallen, St. Gallen, Switzerland.
³⁸ Biosciences Research Institute, School of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain.
³⁹ Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Centre, Dianalund, Denmark.
⁴⁰ Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.
⁴¹ CHU Rennes, Hôpital Sud, Service de Génétique Clinique, Univ Rennes, CNRS IGDR UMR 6290, Centre de référence Anomalies du développement CLAD-Ouest, ERN ITHACA, Rennes, France.
⁴² Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
⁴³ Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
⁴⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁴⁵ Mitochondrial Medicine & Neurogenetics, Cleveland Clinic, Cleveland, Ohio, USA.
⁴⁶ Institute for Genomic Medicine, Columbia University Medical Center, New York City, New York, USA.
⁴⁷ Precision Genomics Laboratory, Columbia University Irving Medical Center, New York City, New York, USA.
⁴⁸ Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
⁴⁹ Baylor Genetics Laboratories, Houston, Texas, USA.
⁵⁰ University Clinic of Genetics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
⁵¹ Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, Australia.

PMID: 34859529
DOI: 10.1002/humu.24308

Free article

The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder

Smitha Kumble et al. Hum Mutat. 2022 Feb.

Free article

. 2022 Feb;43(2):266-282.

doi: 10.1002/humu.24308. Epub 2021 Dec 11.

Authors

Affiliations

¹ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.
² Department of Clinical Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
³ Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
⁵ Department of Review Analysis, GeneDx LLC, Maryland, USA.
⁶ Rare Disease Institute, Children's National Hospital, Washington, District of Columbia, USA.
⁷ Department of Pediatrics, Columbia University Irving Medical Center, New York City, New York, USA.
⁸ Division of Genetics, Joe DiMaggio Children's Hospital, Hollywood, Florida, USA.
⁹ Department of Pediatrics, University Hospital Hvidovre, Hvidovre, Denmark.
¹⁰ Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
¹¹ Division of Genetic Medicine, Lausanne University Hospital and University of Lausanne (CHUV), Lausanne, Switzerland.
¹² Stead Family Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.
¹³ Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, Maryland, USA.
¹⁴ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁵ Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁶ Deptartment of Pediatrics, Genetic Medicine, UCSF/Fresno, Fresno, California, USA.
¹⁷ Service de pédiatrie et de génétique clinique, CHU Rennes, Rennes, France.
¹⁸ INSERM UMR1231 Equipe GAD, Université de Bourgogne, Dijon, France.
¹⁹ Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
²⁰ Division of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
²¹ Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France.
²² Inserm UMR1231 GAD, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.
²³ Internal Medicine & Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
²⁴ Laboratoire de biologie médicale multisites Seqoia-FMG2025, Paris, France.
²⁵ Service Génétique des Tumeurs, Gustave Roussy, Villejuif, France.
²⁶ Nemours Children's Hospital, Orlando, Florida, USA.
²⁷ Center for Experimental Neurotherapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
²⁸ Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Idipaz, Madrid, Spain.
²⁹ Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, U753), Instituto Carlos III, Madrid, Spain.
³⁰ Texas Children's Hospital, Houston, Texas, USA.
³¹ Molecular Modelling Group, Severo Ochoa Molecular Biology Centre (CBMSO, CSIC-UAM), Madrid, Spain.
³² Clinical Genomics Program, GeneDx, Maryland, USA.
³³ Regional Department of Genetics, Southern California Kaiser Permanente Medical Group, Pasadena, California, USA.
³⁴ Division of Clinical Genetics, Columbia University Irving Medical Center, New York City, New York, USA.
³⁵ Divison of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³⁶ Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
³⁷ Department of Neuropediatrics, Childrens Hospital of Eastern Switzerland St. Gallen, St. Gallen, Switzerland.
³⁸ Biosciences Research Institute, School of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain.
³⁹ Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Centre, Dianalund, Denmark.
⁴⁰ Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.
⁴¹ CHU Rennes, Hôpital Sud, Service de Génétique Clinique, Univ Rennes, CNRS IGDR UMR 6290, Centre de référence Anomalies du développement CLAD-Ouest, ERN ITHACA, Rennes, France.
⁴² Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
⁴³ Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
⁴⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁴⁵ Mitochondrial Medicine & Neurogenetics, Cleveland Clinic, Cleveland, Ohio, USA.
⁴⁶ Institute for Genomic Medicine, Columbia University Medical Center, New York City, New York, USA.
⁴⁷ Precision Genomics Laboratory, Columbia University Irving Medical Center, New York City, New York, USA.
⁴⁸ Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
⁴⁹ Baylor Genetics Laboratories, Houston, Texas, USA.
⁵⁰ University Clinic of Genetics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
⁵¹ Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, Australia.

PMID: 34859529
DOI: 10.1002/humu.24308

Abstract

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.

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References

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The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder

Affiliations

The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder

Authors

Affiliations

Abstract

References

REFERENCES

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials