Presenter Status
Fellow
Abstract Type
Research
Primary Mentor
Carol Saunders
Start Date
11-5-2021 11:30 AM
End Date
11-5-2021 1:30 PM
Presentation Type
Poster Presentation
Description
Background: In recent years, wide implementation of research and clinical next generation sequencing has led to an astonishing number of novel disease-gene assertions. Recently, loss of function variants in JARID2 were reported in 16 patients with a clinically distinct neurodevelopmental phenotype that consisted of neurodevelopmental delay, intellectual disability (ID), learning disability, autism and behavioral abnormalities. Dysmorphic features were seen in most patients and included high anterior hairline, deep-set eyes, full lips, broad forehead, bulbous nasal tip, or depressed nasal bridge. Cleft lip/palate was observed in only 1/16 patients. Most cases were de novo, with only one inherited case from an affected parent.
Objectives/Goal: The goal of the study was to identify additional patients with JARID2 variants and further characterize the genotypic and phenotypic spectrum of the disease.
Methods/Design: We searched our internal database for patients with single nucleotide or copy number variants in JARID2. In one case, we further used long-range PacBio sequencing to aid in the interpretation of an intragenic duplication in JARID2.
Results: We present a case series of 9 patients with single nucleotide or copy number variants affecting JARID2. Full gene deletions, intragenic deletions and duplications ranging from 60 kb to 9.4 Mb were detected in 6 patients by clinical microarray. Long range next generation sequencing of one duplication carrier suggested that it was in tandem. Three patients with loss of function single nucleotide variants were detected by clinical NGS. Parental testing was not available for most cases, but family histories of learning disability and behavior abnormalities were noted. In two cases, the variant was inherited from a mildly affected parent. Most patients had speech delays, global developmental delays and learning disability (7/9). Behavioral anomalies including autism, stereotypies, tics, repetitive movements and attention deficit were seen in 4/7 patients. Heterogeneous neurological abnormalities were observed in 4/7 patients and included ID, gait disturbances, strabismus, hypotonia, hearing loss, seizures and abnormal MRI findings. Dysmorphic features were observed in 6/9 patients. Several patients and at-risk relatives showed cleft lip/palate.
Conclusions: We provide further evidence of a gene-disease association for JARID2 in intellectual disability. Our results are consistent with previously reported findings and reinforce that the phenotype may be variable, mild, and inherited from a mildly affected parent. In addition, our data shows that cleft lip/palate could be more commonly seen than previously reported in patients with JARID2 variants. We also demonstrate the utility of long-range sequencing in resolving structural organization of intragenic duplications.
MeSH Keywords
Intellectual disability; JARID2; Clinical genetics
Included in
Higher Education and Teaching Commons, Medical Education Commons, Nervous System Diseases Commons, Pediatrics Commons, Science and Mathematics Education Commons
Phenotypic characterization of JARID2-related intellectual disability: A case series
Background: In recent years, wide implementation of research and clinical next generation sequencing has led to an astonishing number of novel disease-gene assertions. Recently, loss of function variants in JARID2 were reported in 16 patients with a clinically distinct neurodevelopmental phenotype that consisted of neurodevelopmental delay, intellectual disability (ID), learning disability, autism and behavioral abnormalities. Dysmorphic features were seen in most patients and included high anterior hairline, deep-set eyes, full lips, broad forehead, bulbous nasal tip, or depressed nasal bridge. Cleft lip/palate was observed in only 1/16 patients. Most cases were de novo, with only one inherited case from an affected parent.
Objectives/Goal: The goal of the study was to identify additional patients with JARID2 variants and further characterize the genotypic and phenotypic spectrum of the disease.
Methods/Design: We searched our internal database for patients with single nucleotide or copy number variants in JARID2. In one case, we further used long-range PacBio sequencing to aid in the interpretation of an intragenic duplication in JARID2.
Results: We present a case series of 9 patients with single nucleotide or copy number variants affecting JARID2. Full gene deletions, intragenic deletions and duplications ranging from 60 kb to 9.4 Mb were detected in 6 patients by clinical microarray. Long range next generation sequencing of one duplication carrier suggested that it was in tandem. Three patients with loss of function single nucleotide variants were detected by clinical NGS. Parental testing was not available for most cases, but family histories of learning disability and behavior abnormalities were noted. In two cases, the variant was inherited from a mildly affected parent. Most patients had speech delays, global developmental delays and learning disability (7/9). Behavioral anomalies including autism, stereotypies, tics, repetitive movements and attention deficit were seen in 4/7 patients. Heterogeneous neurological abnormalities were observed in 4/7 patients and included ID, gait disturbances, strabismus, hypotonia, hearing loss, seizures and abnormal MRI findings. Dysmorphic features were observed in 6/9 patients. Several patients and at-risk relatives showed cleft lip/palate.
Conclusions: We provide further evidence of a gene-disease association for JARID2 in intellectual disability. Our results are consistent with previously reported findings and reinforce that the phenotype may be variable, mild, and inherited from a mildly affected parent. In addition, our data shows that cleft lip/palate could be more commonly seen than previously reported in patients with JARID2 variants. We also demonstrate the utility of long-range sequencing in resolving structural organization of intragenic duplications.
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