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Identifying new genotype/phenotype correlations for individuals carrying deleterious RERE variants

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
RERE is located within the proximal critical region for 1p36 deletion syndrome and encodes a nuclear receptor co-regulator that plays essential roles in development. Heterozygous pathogenic RERE variants cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH; MIM# 605226). Previous studies have implicated missense variants affecting RERE's Atrophin-1 domain with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared to loss-of-function variants, and a recurrent c.4313_4318dupTCCACC variant has been shown to cause phenotypes reminiscent of CHARGE syndrome.

Methods:
We gathered clinical and molecular data from 27 additional individuals with deleterious RERE variants, establishing a cohort of 51 individuals. We evaluated this cohort to identify novel genotype/phenotype correlations.

Results:
Loss-of-function variants were generally associated with milder phenotypes that included developmental delay, intellectual disability, autism spectrum disorder, speech apraxia/dyspraxia, occasional structural brain anomalies, and ventricular septal defects. These variants were sometimes inherited from asymptomatic individuals, suggesting that RERE haploinsufficiency spans a broad phenotypic range and is incompletely penetrant.

 

De novo missense variants and small in-frame deletions/duplications affecting a histidine-rich region within the Atrophin-1 domain were associated with distinctive phenotypic patterns of developmental delay, intellectual disability, autism spectrum disorder, structural brain anomalies—notably a thin corpus callosum—and congenital heart defects. Small in-frame duplications affecting this region caused neurodevelopmental, ophthalmologic, auditory, craniofacial, cardiac, and genitourinary abnormalities reminiscent of CHARGE syndrome. Neurodevelopmental phenotypes were the only consistent feature associated with small, in-frame deletions affecting this area.

 

In contrast to murine models of RERE deficiency, kidney anomalies are rare in individuals with NEDBEH.

 

Conclusion:
In this study, we double the cohort of individuals described with damaging RERE variants, demonstrate that RERE haploinsufficiency is associated with incomplete penetrance, and identify novel genotype/phenotype correlations. Based on these data, we propose new screening protocols for neuroimaging, hearing evaluations, developmental assessments, echocardiography, and renal ultrasound evaluations tailored to specific variant types.

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