# Homozygous DHCR7 p.Val330Met Variant Associated with Mild Non-Syndromic Intellectual Disability and Elevated Serum 7-Dehydrocholesterol Levels in Two Siblings

## TL;DR

Two siblings with mild intellectual disability and elevated 7-DHC levels were found to have a DHCR7 gene variant, suggesting a new link to non-syndromic intellectual disability.

## Contribution

The study identifies a novel DHCR7 variant associated with non-syndromic intellectual disability without typical SLOS features.

## Key findings

- Siblings with mild developmental delay and elevated 7-DHC levels had the DHCR7 c.988G>A variant.
- The variant is highly conserved and has a population allele frequency of 0.04%.
- No other causes for intellectual disability were found in the siblings.

## Abstract

Biallelic pathogenic variants in DHCR7 result in decreased activity of 7-dehydrocholesterol (7-DHC) reductase, which converts 7-DHC to cholesterol, and causes Smith–Lemli–Opitz syndrome (SLOS). Elevated serum 7-DHC levels are indicative of SLOS as are intellectual disability (ID), growth retardation, microcephaly, craniofacial anomalies, and 2–3 toe syndactyly. Additional congenital malformations may be present in SLOS, and broad clinical variability has been recognized in SLOS. Rarely, biallelic pathogenic DHCR7 variants were reported with low-normal and normal intelligence quotient (IQ) and development. We report here a pair of siblings with mild global developmental delay, infrequent epileptic seizures, and elevated serum 7-DHC levels, associated with the homozygous DHCR7 variant c.988G>A (p.Val330Met). Remarkably, neither sibling displayed congenital anomalies nor dysmorphisms. Quattro-exome sequencing performed for global delay and mild ID in both siblings did not identify other ID causes. c.988G>A affects a highly conserved amino acid and displays a relatively high global population allele frequency of 0.04%, with absence of homozygotes from the population database gnomADv4.1.0. Our observation leads us to suggest that DHCR7 variant c.988G>A and other DHCR7 variants might be generally considered as underlying non-syndromic ID.