The clinical and molecular spectrum of
            <i>QRICH1</i>
            associated neurodevelopmental disorder

Kumble, Smitha; Levy, Amanda M.; Punetha, Jaya; Gao, Hua; Mew, Nicholas Ah; Anyane‐Yeboa, Kwame; Benke, Paul J.; Berger, Sara M.; Bjerglund, Lise; Campos‐Xavier, Belinda; Ciliberto, Michael A.; Cohen, Julie S.; Comi, Anne M.; Curry, Cynthia J.; Damaj, Léna; Denommé‐Pichon, Anne‐Sophie; Emrick, Lisa; Faivre, Laurence; Fasano, Mary Beth; Fiévet, Alice; Finkel, Richard S.; García‐Miñaúr, Sixto; Gerard, Amanda; Gómez‐Puertas, Paulino; Sacoto, María J. Guillen; Hoffman, Trevor L.; Howard, Lillian; Iglesias, Alejandro; Izumi, Kosuke; Larson, Austin; Leiber, Anja; Lozano, Reymundo; Marcos‐Alcalde, Íñigo; Mintz, Cassie; Mullegama, Sureni V; Møller, Rikke S.; Odent, Sylvie; Oppermann, Henry; Østergaard, Elsebet; Pacio‐Míguez, Marta; Palomares‐Bralo, María; Parikh, Sumit; Paulson, Anna M; Platzer, Konrad; Posey, Jennifer E.; Potocki, Lorraine; Revah‐Politi, Anya; Rio, Marlène; Ritter, Alyssa; Robinson, Scott; Rosenfeld, Jill A.; Santos‐Simarro, Fernando; Sousa, Sérgio B.; Wéber, Mathys; Xie, Yili; Chung, Wendy K.; Brown, Natasha J; Tümer, Zeynep

doi:10.1002/humu.24308

Cited by 9 publications

(18 citation statements)

References 23 publications

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“…For example, mice knocked out of the VDR had severe colitis and increased intestinal mucosal permeability ( Zhang et al, 2019b ). QRICH1 plays a key role in the unfolded response to endoplasmic reticulum (ER) stress through transcriptional control of protein status, and QRICH1 variants contribute to neurodevelopmental disorders through dysregulation of the ER stress response ( Kumble et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Assessing the effect of interaction between gut microbiome and inflammatory bowel disease on the risks of depression

Qin¹,

Pan²,

Cai³

et al. 2022

Brain, Behavior, & Immunity - Health

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Section: Discussionmentioning

confidence: 99%

Assessing the effect of interaction between gut microbiome and inflammatory bowel disease on the risks of depression

Qin¹,

Pan²,

Cai³

et al. 2022

Brain, Behavior, & Immunity - Health

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“…Overall, 35 different pathological variants have been described until now, with most predicted as protein-truncating variants [5]. However only 4 individuals with inherited pathogenic variants have been described lately, showing paternal inheritance in 3 cases and 1 of maternal inheritance [5]. This report is of a mother and daughter with VEBRAS, associated with a new variant of the QRICH1 gene, NM_017730.3: c.337C>T; p.(Gln113*).…”

Section: Introductionmentioning

confidence: 91%

“…You et al showed the role of QRICH1 in maintaining tissue homeostasis during pathological conditions such as inflammatory or metabolic disorders [4]. Recently, Kumble et al published a study of 38 cases, summarizing all previously known clinical and genetic information about pathogenic QRICH1 variants [5]. Overall, 35 different pathological variants have been described until now, with most predicted as protein-truncating variants [5].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, Kumble et al published a study of 38 cases, summarizing all previously known clinical and genetic information about pathogenic QRICH1 variants [5]. Overall, 35 different pathological variants have been described until now, with most predicted as protein-truncating variants [5]. However only 4 individuals with inherited pathogenic variants have been described lately, showing paternal inheritance in 3 cases and 1 of maternal inheritance [5].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mother and Daughter with Short Stature, Microcephaly, Mild Dysmorphic Features, and Learning Disabilities Due to Ververi-Brady Syndrome Associated with a New Variant of the QRICH1 Gene

et al. 2023

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Background:Ververi-Brady syndrome (VEBRAS) is an autosomal dominant condition associated with short stature, microcephaly, mild dysmorphic features, and learning disabilities. It was first described in 2018, and only 38 cases have been reported since then. All patients have mutation in the Glutamine-rich protein 1 (QRICH1) gene, yet clinical presentation has a broad spectrum and continues to expand. This report is of a mother and daughter pair with VEBRAS, associated with a new variant of the QRICH1 gene, NM_017730.3: c.337C>T; p.(Gln113*), and few previously undescribed phenotypic features. Case Reports:We present 2 new cases, a mother and daughter, with novel heterozygous nonsense variant NM_017730.3: c.337C>T; p.(Gln113*). The daughter was referred to a geneticist at the age of 17 years because of seizures, dysmorphic features, and magnetic resonance imaging suggestive of leukodystrophy. In addition to already described clinical features, she had diffuse infantile hemangiomatosis and occipital balding. She was accompanied by her mother, who shared similar phenotypic features, raising suspicion for a similar genetic condition. Unlike the daughter, the mother never had any significant health problems or concerns and described herself as perfectly healthy. Genetic testing was performed in both individuals, and a novel pathogenic QRICH1 variant was discovered. Conclusions:Considering the novelty of VEBRAS, every new clinical case contributes to the enlargement of the VEBRAS cohort, expanding the phenotypical and mutational spectrum, with potential improvement in the further care and observation of probands and their offspring. This report has highlighted the importance of clinical genetics in the identification of familial genetic disorders with complex phenotypes.

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“…The copyright holder for this this version posted September 30, 2022. ; https://doi.org/10.1101/2022.09.29.22279724 doi: medRxiv preprint family of proteins includes two additional members, ZMYM4, and QRICH1. Variation in QRICH1 (MIM:617387) has been associated with Ververi-Brady syndrome (MIM:617387), which has features including developmental delay, intellectual disability, non-specific facial dysmorphism, and hypotonia among others 36 .…”

Section: (Which Was Not Certified By Peer Review) Preprintmentioning

confidence: 99%

Deleterious, protein-altering variants in the X-linked transcriptional coregulator ZMYM3 in 22 individuals with a neurodevelopmental delay phenotype

Hiatt

Trajkova

Sebastiano

et al. 2022

Preprint

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Neurodevelopmental disorders (NDDs) often result from highly penetrant variation in one of many genes, including genes not yet characterized. Using the MatchMaker Exchange, we assembled a cohort of 22 individuals with rare, protein-altering variation in the X-linked transcriptional coregulator gene ZMYM3. Most (n=19) individuals were males; 15 males had maternally-inherited alleles, three of the variants in males arose de novo, and one had unknown inheritance. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n=21) are missense, two of which are recurrent. Three unrelated males were identified with inherited variation at R441, a site at which variation has been previously reported in NDD-affected males, and two individuals have de novo variation at R1294. All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is highly expressed in the brain, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one mutant, ZMYM3R1274W, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to support a conclusive causative role for variation in ZMYM3 in disease, the totality of the evidence, including the presence of recurrent variation, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally-confirmed functional effects, strongly supports ZMYM3 as a novel NDD gene.

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The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder

Cited by 9 publications

References 23 publications

Assessing the effect of interaction between gut microbiome and inflammatory bowel disease on the risks of depression

Assessing the effect of interaction between gut microbiome and inflammatory bowel disease on the risks of depression

Mother and Daughter with Short Stature, Microcephaly, Mild Dysmorphic Features, and Learning Disabilities Due to Ververi-Brady Syndrome Associated with a New Variant of the QRICH1 Gene

Deleterious, protein-altering variants in the X-linked transcriptional coregulator ZMYM3 in 22 individuals with a neurodevelopmental delay phenotype

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