A novel KDM6A c.2429dup mutation causing kabuki syndrome type 2 identified in a fetus with increased nuchal...

Kabuki syndrome (KS) is a rare, multiple congenital anomaly syndrome, characterized by dysmorphic facial features, skeletal anomalies, dermatoglyphic abnormalities, developmental delay, mild-to-moderate intellectual disability, and postnatal growth restriction. KS type 1 (KS1, OMIM 147920) is caused by autosomal dominant pathogenic mutations in KMT2D, and KS type 2 (KS2, OMIM 300867) is caused by X-linked dominant pathogenic mutations in KDM6A.

To identify the genetic etiologies in a fetus with increased nuchal translucency (NT) observed by ultrasound at 11⁺⁶weeks of gestation.

Chromosomal microarray analysis (CMA) and trio-exome sequencing (trio-ES) were performed on amniotic fluid sample to investigate the potential genetic causes. Sanger sequencing was utilized for validation of the candidate variant.

A 28-year-old Chinese pregnant woman was referred for prenatal evaluation due to fetal increased NT (NT = 6.7 mm). CMA yielded a normal result, with no pathogenic or likely pathogenic copy number variants, or mosaicism detected. However, trio-ES identified a novel de novo frameshift mutation (NM_021140.4: c.2429dup (p.Thr811Aspfs*2)) in the KDM6A gene. This variant was classified as pathogenic (PVS1 + PS2_Supporting + PM2_Supporting) based on the American College of Medical Genetics and Genomics guidelines.

The fetus was diagnosed with X-linked dominant KS2. The identification of this novel frameshift variant, together with the first report of increased NT as a prenatal feature, enriched both the mutation spectrum and prenatal phenotypic spectrum of KS2. These findings underscore the diagnostic utility of ES for fetuses with increased NT, especially when CMA yields normal results.