Novel biallelic LSS variants in autosomal recessive hypotrichosis simplex: insights from a multi-omics approach.

Hypotrichosis simplex is a rare form of non-syndromic hereditary alopecia characterized by childhood-onset diffuse and progressive scalp and body hair loss. Several genes have been identified as being associated with hypotrichosis simplex, including LPAR6, LIPH, DSG4, SNRPE, APCDD1, and LSS, among others. In this study, by sequencing peripheral blood DNA from probands, four pairs of novel biallelic variants of LSS (c.1335dupT; p.Thr446Tyrfs*10 and c.893-175G > A, c.1025 T > G; p.Ile342Ser and c.386C > A; p.Arg129Gln, c.1054G > A; p.Gly352Arg and c.1594G > C; p.Glu532Gln, c.385C > T; p.Arg129Trp and c.1303G > C; p.Arg435Cys) were identified in four Chinese families with autosomal recessive hypotrichosis simplex, among which a deep intronic pathogenic variant (c.893-175G > A) at a non-canonical splice site was identified by integrated analysis of whole genome sequencing and RNAseq. LSS encodes lanosterol synthase, a key enzyme that plays a critical role in steroid metabolism and is essential for hair follicle development. Molecular structural modeling also revealed significant adverse effects of the identified variants as well. The thickened epidermis, absence of hair follicles, and sebaceous gland hyperplasia were present by histopathological staining in the available tissue from the core family. The non-canonical pathogenic variant leads not only to abnormal mRNA splicing but also to decreased expression of LSS. Our results demonstrate the pathogenicity of LSS variants in causing hypotrichosis simplex and highlight the significance of combined application of multiple sequencing technologies for accurate disease diagnosis.