Objective Recessive X-linked ichthyosis (RXLI) caused by deficiency of the steroid sulfatase gene ( STS) has a reported prevalence of 1/2000 to 1/6000. The present study aimed to characterize the phenotypes and genotypes of two Chinese families with RXLI. Methods The patients were referred to the Family Planning Research Institute of Hunan Province for genetic counseling. Their skin phenotypes were photographed, and venous blood was drawn and used for chromosomal microarray analysis (CMA). Results The skin phenotype of the proband from the first family was characterized by generalized skin dryness and scaling, with noticeable dark brown, polygonal scales on his trunk and extensor surfaces of his extremities. The proband from the second family had an atypical phenotype showing mild skin dryness over his entire body, slight scaling on his abdomen, and small skin fissures on his arms and legs. No mental disability or developmental anomaly was noted in either proband. CMA revealed that both probands carried a 1.4-Mb deletion on chromosome Xp22.31 involving four Online Mendelian Inheritance in Man-listed genes including STS. Conclusions Our findings add knowledge to the genotype and phenotype spectrum of RXLI, which may be helpful in genetic counseling and prenatal diagnosis.

The signal-induced proliferation-associated 1-like 3 (SIPA1L3) gene that encodes a putative Rap GTPase-activating protein (RapGAP) has been associated with congenital cataract and eye development abnormalities. However, our current understanding of the mutation spectrum of SIPA1L3 associated with eye defects is limited. By using whole-exome sequencing plus Sanger sequencing validation, we identified a novel heterozygous c.1871A > G (p.Lys624Arg) variation within the predicted RapGAP domain of SIPA1L3 in the proband with isolated juvenile-onset cataracts from a three-generation Chinese family. In this family, the proband's father and grandmother were also heterozygous for the c.1871A > G variation and affected by cataracts varying in morphology, severity, and age of onset. Sequence alignment shows that the Lys 624 residue of SIPA1L3 is conserved across the species. Based on the resolved structure of Rap1–Rap1GAP complex, homology modeling implies that the Lys 624 residue is structurally homologous to the Lys 194 of Rap1GAP, a highly conserved lysine residue that is involved in the interface between Rap1 and Rap1GAP and critical for the affinity to Rap·GTP. We reasoned that arginine substitution of lysine 624 might have an impact on the SIPA1L3-Rap·GTP interaction, thereby affecting the regulatory function of SIPA1L3 on Rap signaling. Collectively, our finding expands the mutation spectrum of SIPA1L3 and provides new clues to the molecular mechanisms of SIPA1L3-related cataracts. Further investigations are warranted to validate the functional alteration of the p.Lys624Arg variant of SIPA1L3.