JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

Verberne, Eline A.; Goh, Shuxiang; England, Jade; Ginkel, Manon van; Rafael-Croes, Louise; Maas, Saskia M.; Polstra, Abeltje M.; Zárate, Yuri A.; Bosanko, Katherine A.; Pechter, Kieran B.; Bedoukian, Emma; Izumi, Kosuke; Chaudhry, Ayeshah; Robin, Nathaniel H.; Boothe, Megan; Lippa, Natalie; Aggarwal, Vimla S.; Vivo, Darryl C. De; Lehman, Anna; Study, Causes; Stöckler, Sylvia; Bruel, Ange Line; Isidor, Bertrand; Lemons, Jennifer; Rodriguez-Buritica, David; Richmond, Christopher; Stark, Zornitza; Agrawal, Pankaj B.; Kooy, R. Frank; Meuwissen, Marije; Koolen, David A.; Pfundt, Rolf; Liedén, Agne; Anderlid, Britt Marie; Glatz, Dagmar; Mannens, Marcel M.A.M.; Bakshi, Madhura; Mallette, Frédérick A.; Haelst, Mieke M. van; Campeau, Philippe M.

doi:10.1038/s41436-020-00992-z

Cited by 17 publications

(32 citation statements)

References 41 publications

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“…However, if inherited, this variant would still not be dismissed given the variable severity seen in individuals with Overall, the individuals reported here have features consistent with the previous cohort including delays, behavioral and neurological abnormalities, dysmorphic features, and congenital anomalies, strengthening the JARID2-disease association (Table S1). 6 As expected for rare disorders, some features were observed for the first time in our cohort, while others were previously reported but uncommon. We observed palatal abnormalities in 3/7 patients with a JARID2 likely pathogenic or pathogenic variants, whereas this phenotype was seen in only 1/16 patient in the previously reported cohort.…”

Section: Discussionsupporting

confidence: 80%

“…We observed palatal abnormalities in 3/7 patients with a JARID2 likely pathogenic or pathogenic variants, whereas this phenotype was seen in only 1/16 patient in the previously reported cohort. 6 The association of JARID2 with palate formation is supported by its high expression in the epithelia of mouse palatal shelves, as well as several variants showing significant association with non-syndromic cleft lip/palate. [2][3][4] In addition to palatal abnormalities, heart defects, including atrial septal defect, VSD and left pulmonary artery stenosis, were seen in 43% of our cases (3/7), versus only 6% (1/16) in the previous cohort.…”

Section: Discussionmentioning

confidence: 98%

“…The diagnostic variant spectrum included 3 SNVs and 2 intragenic deletions classified as likely pathogenic or pathogenic according to ACMG interpretation guidelines 9 . Importantly, we note the overall high prevalence of CNVs in JARID2 : of all affected individuals reported to date, including this cohort, 9/23 (39%) have intragenic deletions 6 . This highlights the importance of exon‐level copy number evaluation.…”

Section: Discussionmentioning

confidence: 99%

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Phenotypic expansion and variable expressivity in individuals with JARID2‐related intellectual disability: A case series

et al. 2022

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Loss of function variants in JARID2 were recently reported in 16 patients with a neurodevelopmental disorder characterized by delays, intellectual and learning disability, autism, behavioral abnormalities, and dysmorphic features. Most cases were de novo, with only one variant inherited from an affected parent. Here, we present seven additional individuals from five families with pathogenic or likely pathogenic JARID2 variants, confirming this gene-disease association and highlighting palatal abnormalities and heart defects as part of the phenotype. In addition, we report inheritance of JARID2 variants from mildly affected parents, demonstrating the variable expressivity of the disease. We also note the high prevalence of intragenic JARID2 copy number variants, emphasizing the importance of exon-level analysis.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Phenotypic expansion and variable expressivity in individuals with JARID2‐related intellectual disability: A case series

et al. 2022

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“…The patient cohort included a total of eleven individuals (six males and five females) with variants in JARID2 , of which seven (patient 1–5, 9 and 10) have been previously described in the literature [ 1 ]. All patients were identified in a clinical diagnostic setting.…”

Section: Methodsmentioning

confidence: 99%

“…JARID2 (Jumonji, AT Rich Interactive Domain 2; OMIM 601594) haploinsufficiency has been associated with a clinically distinct neurodevelopmental syndrome [ 1 , 2 , 3 ]. It is characterized by developmental delay, cognitive impairment (ranging from borderline intellectual functioning to severe intellectual disability), hypotonia, autistic features and behavior abnormalities.…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation Signature for JARID2-Neurodevelopmental Syndrome

Verberne

Laan

Haghshenas

et al. 2022

IJMS

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JARID2 (Jumonji, AT Rich Interactive Domain 2) pathogenic variants cause a neurodevelopmental syndrome, that is characterized by developmental delay, cognitive impairment, hypotonia, autistic features, behavior abnormalities and dysmorphic facial features. JARID2 encodes a transcriptional repressor protein that regulates the activity of various histone methyltransferase complexes. However, the molecular etiology is not fully understood, and JARID2-neurodevelopmental syndrome may vary in its typical clinical phenotype. In addition, the detection of variants of uncertain significance (VUSs) often results in a delay of final diagnosis which could hamper the appropriate care. In this study we aim to detect a specific and sensitive DNA methylation signature for JARID2-neurodevelopmental syndrome. Peripheral blood DNA methylation profiles from 56 control subjects, 8 patients with (likely) pathogenic JARID2 variants and 3 patients with JARID2 VUSs were analyzed. DNA methylation analysis indicated a clear and robust separation between patients with (likely) pathogenic variants and controls. A binary model capable of classifying patients with the JARID2-neurodevelopmental syndrome was constructed on the basis of the identified episignature. Patients carrying VUSs clustered with the control group. We identified a distinct DNA methylation signature associated with JARID2-neurodevelopmental syndrome, establishing its utility as a biomarker for this syndrome and expanding the EpiSign diagnostic test.

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Genetic care in geographically isolated small island communities: 8 years of experience in the Dutch Caribbean

Verberne

Westermann

Vries

et al. 2022

American J of Med Genetics Pt A

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Worldwide, there are large inequalities in genetic service delivery. In 2011, we established a bi-annual joint pediatric-genetics clinic with a visiting clinical geneticist in the Dutch Caribbean. This retrospective study evaluates the yield of diagnostic testing and the clinical utility of a diagnosis for patients with rare diseases on these relatively isolated, resource-limited islands. A total of 331 patients that were referred to the clinical geneticist between November 2011 and November 2019 and had genetic testing were included in this study. A total of 508 genetic tests were performed on these patients. Microarray, next-generation sequencing gene panels, and single-gene analyses were the most frequently performed genetic tests. A molecularly confirmed diagnosis was established in 33% of patients (n = 108). Most diagnosed patients had single nucleotide variants or small insertions and/or deletions (48%) or copy number variants (34%). Molecular diagnostic

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JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

Cited by 17 publications

References 41 publications

Phenotypic expansion and variable expressivity in individuals with JARID2‐related intellectual disability: A case series

Phenotypic expansion and variable expressivity in individuals with JARID2‐related intellectual disability: A case series

DNA Methylation Signature for JARID2-Neurodevelopmental Syndrome

Genetic care in geographically isolated small island communities: 8 years of experience in the Dutch Caribbean

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