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Background <p>Neurodevelopmental Disorder with or without anomalies of the Brain, Eye, or Heart (NEDBEH) is an ultra-rare autosomal dominant disorder caused by heterozygous pathogenic variants in RERE, a gene encoding a nuclear receptor coregulator essential for retinoic acid signaling and embryonic development. Fewer than 60 affected individuals have been reported to date, and the phenotypic spectrum remains incompletely defined.</p> Methods <p>Two unrelated pediatric patients were evaluated clinically and by multidisciplinary investigations including echocardiography, brain MRI, renal ultrasound, and ophthalmologic and audiologic assessments. G-banded karyotyping was performed in both. Exome sequencing (CentoXome MOx) with NGS-based CNV assessment and uniparental disomy screening was followed by parental targeted testing. Variants were classified according to ACMG/AMP guidelines.</p> Results <p>Patient 1, a 6-year-old male born to non-consanguineous parents, harbored a novel de novo heterozygous nonsense variant (NM_001042681.1:c.3535C&gt;T, p. (Arg1179*) and presented with a mild phenotype comprising congenital hypothyroidism, ventricular septal defect, pulmonary artery stenosis, and isolated speech delay. Patient 2, a 7-year-old female born to consanguineous parents, carried the recurrent de novo in-frame duplication (c.4313_4318dupTCCACC, p.(Leu1438_His1439dup) and presented with a severe multisystem phenotype including spastic quadriplegic cerebral palsy, complex congenital heart disease, unilateral renal agenesis, and profound global developmental delay.</p> Conclusion <p>These two cases expand the clinical and molecular spectrum of RERE-related NEDBEH, illustrate the divergent outcomes associated with loss-of-function versus in-frame Atrophin-1 domain variants, and underscore the value of early exome sequencing in children with complex multisystem involvement.</p>

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Phenotypic Expansion of RERE-Related Disorder (NEDBEH): A Case Report of Two Families

  • 期刊论文

  • 发表日期：

    2026年6月20日

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  • Iman Almiran,
  • Emtithal Aljishi,
  • Hisham Y. Hassan,
  • Haya Alkhayyat

摘要

Background

Neurodevelopmental Disorder with or without anomalies of the Brain, Eye, or Heart (NEDBEH) is an ultra-rare autosomal dominant disorder caused by heterozygous pathogenic variants in RERE, a gene encoding a nuclear receptor coregulator essential for retinoic acid signaling and embryonic development. Fewer than 60 affected individuals have been reported to date, and the phenotypic spectrum remains incompletely defined.

Methods

Two unrelated pediatric patients were evaluated clinically and by multidisciplinary investigations including echocardiography, brain MRI, renal ultrasound, and ophthalmologic and audiologic assessments. G-banded karyotyping was performed in both. Exome sequencing (CentoXome MOx) with NGS-based CNV assessment and uniparental disomy screening was followed by parental targeted testing. Variants were classified according to ACMG/AMP guidelines.

Results

Patient 1, a 6-year-old male born to non-consanguineous parents, harbored a novel de novo heterozygous nonsense variant (NM_001042681.1:c.3535C>T, p. (Arg1179*) and presented with a mild phenotype comprising congenital hypothyroidism, ventricular septal defect, pulmonary artery stenosis, and isolated speech delay. Patient 2, a 7-year-old female born to consanguineous parents, carried the recurrent de novo in-frame duplication (c.4313_4318dupTCCACC, p.(Leu1438_His1439dup) and presented with a severe multisystem phenotype including spastic quadriplegic cerebral palsy, complex congenital heart disease, unilateral renal agenesis, and profound global developmental delay.

Conclusion

These two cases expand the clinical and molecular spectrum of RERE-related NEDBEH, illustrate the divergent outcomes associated with loss-of-function versus in-frame Atrophin-1 domain variants, and underscore the value of early exome sequencing in children with complex multisystem involvement.