Preimplantation genetic testing for KIT-associated pigmentary monogenic diseases

This study addresses the genetic diagnosis and reproductive intervention for families affected by KIT-related pigmentary disorders, which can manifest as either piebaldism due to loss-of-function variants or hyperpigmentation due to gain-of-function variants. We recruited three Chinese families presenting with these distinct phenotypes to identify pathogenic variants and prevent intergenerational transmission. Whole exome sequencing and Sanger sequencing identified three heterozygous KIT variants: a known missense variant (c.2485G>C) in family 1 causing hyperpigmentation and generalized lentigines, and two novel null variants (c.2736_2737insT and c.2664del) in families 2 and 3 causing piebaldism. To assist these families, we implemented a comprehensive preimplantation genetic testing (PGT) for monogenic diseases and aneuploidies. This approach successfully identified euploid embryos free of pathogenic variants for transfer. Uniquely, in family 1, the PGT results were verified during pregnancy using non-invasive prenatal testing for monogenic diseases (NIPT-M) via maternal plasma cell-free DNA analysis, providing a non-invasive confirmatory screen and potentially reducing the need for invasive procedures. Families 1 and 2 successfully delivered healthy infants. This study demonstrates the first successful application of PGT combined with NIPT-M for preventing KIT variant-related pigmentation disorder and enriches the KIT gene's mutational spectrum. This integrated approach provides an effective strategy for preventing the transmission of these monogenic conditions and holds promise for wider application.