A recurrent synonymous KAT6B mutation causes Say‐Barber‐Biesecker/Young‐Simpson syndrome by inducing aberrant splicing

Abstract

Mutations of the histone acetyltransferase-encoding KAT6B gene cause the Say-Barber-Biesecker/Young-Simpson (SBBYS) type of blepharophimosis-"mental retardation" syndromes and the more severe genitopatellar syndrome. The SBBYS syndrome-causing mutations are clustered in the large exon 18 of KAT6B and almost exclusively lead to predicted protein truncation. An atypical KAT6B mutation, a de novo synonymous variant located in exon 16 (c.3147G>A, p.(Pro1049Pro)) was previously identified in three unrelated patients. This exonic mutation was predicted in silico to cause protein truncation through aberrant splicing. Here, we report three additional unrelated children with typical SBBYS syndrome and the KAT6B c.3147G>A mutation. We show on RNA derived from patient blood that the mutation indeed induces aberrant splicing through the use of a cryptic exonic splice acceptor site created by the sequence variant. Our results thus identify the synonymous variant c.3147G>A as a splice site mutation and a mutational hot spot in SBBYS syndrome.

Complex phenotypes blur conventional borders between Say–Barber–Biesecker–Young–Simpson syndrome and genitopatellar syndrome

“…From the few exceptions, one is a recurring synonymous p.Pro1049Pro with a de novo origin that was found to cause partial loss of exon 16 at the RNA level because of a newly created splice acceptor site within this exon with a resulting 127 bp out‐of‐frame deletion leading to a frameshift and subsequent premature stop codon. This reclassified a synonymous variant for a truncating one with a correct description of p.Ala1008Arg fs *62 . In contrast, missense variant p.Trp987Arg was found in only one SBBYSS patient whose parents were not tested, and this variant's possible pathogenic potential was hypothesized via in silico prediction of conservation of the site and its absence in dbSNP .…”

Identifying the KAT6B Mutation via Diagnostic Exome Sequencing to Diagnose Say-Barber-Biesecker-Young-Simpson Syndrome in Three Generations of a Family

“…Until now, 45 SBBYSS, 15 GPS patients, and 5 additional patients with combined phenotypes between the two syndromes have been reported with KAT6B mutation [ 2 3 5 6 7 8 ]. Of those 65 KAT6B mutations, 53 mutations were located in exon 18.…”

“…While GPS mutations were located more proximally in the same exon, losing both domains led to gain-of-function mutation. However recent studies identified mutations more proximal in exon 15, 16, 17 with the typical features of SBBYSS [ 7 8 ]. The mutation occurred in exon 11 in our patient.…”

“…All KAT6B variants identified so far have had heterozygous truncating de novo with no familiar recurrence [ 2 3 5 6 7 8 ]. This report demonstrates a family with an inherited KAT6B missense mutation as opposed to the de novo mutations seen in SBBYSS and GPS.…”

KAT6B-related disorder in a patient with a novel frameshift variant (c.3925dup)

“…Thyroid abnormalities are often observed in patients with KAT6B -related disorders 10 . However, the severity and onset of the phenotype seem to be variable 11–15 . Indeed, the present patient had normal TSH levels at the time of neonatal mass screening.…”