RERE was first reported in relation to autosomal dominant complex neurodevelopmental disorder with or without congenital anomalies in 2016 (Fregeau et al., PMID: 27087320). RERE-related complex neurodevelopmental disorder with or without congenital anomalies most often presents with developmental delay, intellectual disability, and autism. Additional syndromic abnormalities, which are not always present, most commonly involve the eyes, heart, and genitourinary system (i.e. coloboma, optic atrophy/hypoplasia, ventricular septal defect, gastroesophageal reflux disease, hypotonia, etc.). Nine variants (missense, nonsense, and frameshift) that have been reported in 9 probands in 3 publications (PMIDs: 27087320, 29330883, 31452935) are included in this curation. The mechanism of pathogenicity is believed to be LOF. This gene-disease relationship is also supported by a mouse model recapitulating the human phenotype (postnatal growth deficiency, brain hypoplasia, decreased numbers of hippocampal neurons, hearing loss, cardiovascular malformations, ventriculomegaly, incomplete closure of the optic fissure, and renal agenesis) and biochemical function demonstrating RERE’s role in development through retinoic acid signaling (PMIDs: 20164929, 23451234).
In summary, there is definitive evidence supporting the relationship between RERE and autosomal dominant complex neurodevelopmental disorder with or without congenital anomalies. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Approved by the Intellectual Disability and Autism Gene Curation Expert Panel on March 21, 2023.
RERE was first reported in relation to autosomal dominant complex neurodevelopmental disorder with or without congenital anomalies in 2016 (Fregeau et al., PMID: 27087320). RERE-related complex neurodevelopmental disorder with or without congenital anomalies most often presents with developmental delay, intellectual disability, and autism. Additional syndromic abnormalities, which are not always present, most commonly involve the eyes, heart, and genitourinary system (i.e. coloboma, optic atrophy/hypoplasia, ventricular septal defect, gastroesophageal reflux disease, and hypotonia). Nine variants (missense, nonsense, and frameshift) that have been reported in 9 probands in 3 publications (PMIDs: 27087320, 29330883, 31452935) are included in this curation. The mechanism of pathogenicity is believed to be loss of function.
This gene-disease relationship is also supported by a mouse model recapitulating the human phenotype (postnatal growth deficiency, brain hypoplasia, decreased numbers of hippocampal neurons, hearing loss, cardiovascular malformations, ventriculomegaly, incomplete closure of the optic fissure, and renal agenesis) and biochemical function demonstrating RERE’s role in development through retinoic acid signaling (PMIDs: 20164929, 23451234).
In summary, there is definitive evidence supporting the relationship between RERE and autosomal dominant complex neurodevelopmental disorder with or without congenital anomalies. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on March 21, 2023 (SOP Version 9).
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