Zygosity-Dependent Phenotypic Spectrum of RELN-Related Disorders: 10 New Patients and Genotype-Phenotype Correlations Across 48 Kindreds.

RELN

RELN variants whose zygosity modulates severity, from the full recessive phenotype with malformation of cortical development to dominant focal epilepsies

RELN variants produce a continuum of neurodevelopmental phenotypes, from autosomal recessive lissencephaly with cerebellar hypoplasia to autosomal dominant focal epilepsies. The authors performed exome sequencing in 10 affected individuals from eight unrelated consanguineous Iranian families, identifying nine distinct variants: four novel, four previously deposited in ClinVar without a reported affected individual, and c.2015C>T p.(Pro672Leu), reported so far only in heterozygous carriers with dominant epilepsy and here described for the first time in the homozygous state in a patient with the full recessive phenotype. These patients were pooled into a PRISMA systematic review updated to July 2026 covering 28 papers, with all variants reannotated against NM_005045.4 under a single ACMG/AMP framework. The primary cohort comprised 80 individuals from 48 kindreds with 48 distinct variants, of which 41 (85%) were pathogenic or likely pathogenic and five were of uncertain significance. Age at onset was not continuous, with no reported onset between 2.4 and 8 years, and malformations of cortical development were documented in all 32 early-onset individuals and in none of the 23 later-onset individuals with evaluable neuroimaging.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The dichotomy in age at onset, with no case between 2.4 and 8 years, is the most usable finding: it allows prediction at the consultation of whether imaging will show a cortical malformation. One caveat in reading it: the authors themselves stress that zygosity does not explain this separation, since monoallelic carriers appear in both groups. Consanguineous Iranian recruitment mechanically enriches severe homozygous forms, limiting extrapolation of the proportions to a non-consanguineous population, but the uniform ACMG reannotation of all 48 variants is a lasting contribution to interpretation.

Analysis by Dr Thibaut Benquey