Intrafamilial Phenotypic Variability of the p.Cys277Tyr Variant: A Case Report and Review of the Literature.

BACKGROUND

Split-hand/foot malformation (SHFM) is a rare congenital limb anomaly defined by the absence or hypoplasia of the central rays of the autopod. SHFM occurs as an isolated entity or part of genetic syndromes with several causative copy-number variations or monogenic alterations known to be involved in the disease pathomechanism. On the other hand, cleft lip/palate (CL/P) usually results from polygenic and environmental factors, with the complex interplay of both leading to this malformation. Pathogenic variants in have been linked to phenotypically distinct disorders, including Hartsfield syndrome, Kallmann syndrome, Jackson-Weiss syndrome, osteoglophonic dysplasia, and Pfeiffer syndrome. Although pathogenic variants in can contribute to syndromic SHFM or CL/P, their role in isolated SHFM or CL remains poorly described in the literature.

METHODS

We conducted targeted next-generation sequencing (NGS) in the proband with SHFM, followed by segregation analysis in the family members.

RESULTS

In this study, we report an index patient presenting with isolated SHFM and his brother with CL and facial dysmorphism, as well as their father with isolated hyposmia. Targeted next-generation sequencing revealed a previously reported heterozygous missense pathogenic variant in (c.830G>A; p.Cys277Tyr) in both affected siblings and their hyposmic father.

CONCLUSIONS

This study expands the phenotypic spectrum associated with pathogenic variants, emphasizing their involvement in non-syndromic SHFM and CL or isolated hyposmia. Our findings highlight the importance of considering in the molecular diagnosis of isolated SHFM or orofacial clefting, point to the high intrafamilial variability of pathogenic variants, and demonstrate the diagnostic value of targeted NGS in rare congenital malformations.