KBG syndrome is caused by variants in the ANKRD11 gene, consistent with an autosomal dominant inheritance pattern. Most reported disease-causing variants are localized in exon 10 (which is also the biggest exon). Loss-of-function (frameshift, nonsense or indels) variants are most frequently identified, however, some missense variants have also been reported in patients with a clear KBG syndrome phenotype. It has been postulated that all disease-causing variants affect the C-terminal regions of the protein and that the mutant proteins accumulate aberrantly (Walz et al, Hum Genet 2015).
De novo and inherited variants have been identified. Because the clinical features can be very subtle, it’s possible that an affected parent only comes to the attention when the (more severely affected) child has been diagnosed with KBG syndrome.
Individuals with deletions including the ANKRD11 gene may exhibit the same phenotype, although the phenotypic spectrum and severity, including the degree of developmental delay as well as the presence of congenital malformations, may be confounded by the concurrent deletion of other genes.
Germline mosaicism has been reported in at least one family.
Prenatal testing may be considered for pregnancies at increased risk, in families in which the pathogenic variant has been identified. Pre-implantation genetic diagnosis may be offered to such families.