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

Variants in RELN lead to a range of neurodevelopmental phenotypes, from autosomal recessive lissencephaly with cerebellar hypoplasia (LCH) (LIS2) to autosomal dominant focal epilepsies. We carried out exome sequencing (ES) on 10 affected individuals from eight unrelated Iranian families with consanguinity. Nine distinct variants were identified: Four are novel; four had been deposited in ClinVar without a reported affected individual; and the ninth, c.2015C>T, p.(Pro672Leu), had been reported only in heterozygous carriers with dominant epilepsy. In this study, we report the variant for the first time in the homozygous state, in a patient with the full recessive phenotype. The patients were pooled in a systematic review following PRISMA, updated to July 2026, with 28 papers, and all variants were reannotated against NM_005045.4, under a single ACMG/AMP framework. The primary cohort comprised 80 individuals from 48 kindreds (70 previously reported, 10 new) with 48 distinctive variants, of which 41 (85%) were pathogenic or likely pathogenic and five were variants of uncertain significance; two balanced rearrangements were not in either the sequence-variant or copy-number frameworks; and 16 individuals from nine kindreds with monoallelic candidate or susceptibility variants were analyzed separately. The age of onset was not continuous with no reports of onsets between 2.4 and 8 years. Zygosity did not account for this separation because monoallelic individuals occurred in both onset groups; in contrast, malformations of cortical development were documented in all 32 early-onset individuals and in none of the 23 later onset individuals with evaluable neuroimaging. ES was the diagnostic method in 65% of individuals. Thus, zygosity contributes to the phenotypic severity in a broad spectrum of RELNopathies and supports carrier testing and reproductive counseling in consanguineous families.