Biallelic pathogenic variants in CRLS1 were detected in all four patients. Homozygous missense variant was identified in the first three Lebanese patients: Chr20(GRCh38): g.6009794T>A, NM_019095.5: c.326T>A, resulting in an ile109-to-asn (I109N) substitution. The c.326T>A variant is rare in gnomAD v.2.1.1, with only one allele identified (1/251152 alleles) and an allele frequency of 0.00039%. The CRLS1 Ile109Asn substituted amino acid is highly conserved across a wide range of animal species (GERP score of 5.4) and the substitution of a non-polar isoleucine with a polar asparagine at the start of a highly conserved transmembrane domain could affect stability or membrane localization of CRLS1.
Compound heterozygous variants were detected in the fourth patient: NM_019095.6: c.515C>A, p.(Ala172Asp) and c.649C>T, p.(Leu217Phe). The c.515C>A variant occurs at a conserved site (GERP score of 6) and is absent from gnomAD. The c.649C>T variant occurs at a conserved site (GERP score of 6) and is rare in gnomAD v.2.1.1, with only four alleles identified (4/245604 alleles) and an allele frequency of 0.0016%. Neither variant has been observed in the homozygous state in the gnomAD database.
CRLS1