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.
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.