Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis

Abstract

Intellectual disability (ID) is a common neurodevelopmental disorder exhibiting extreme genetic heterogeneity, and more than 500 genes have been implicated in Mendelian forms of ID. We performed exome sequencing in a large family affected by an autosomal-dominant form of mild syndromic ID with ptosis, growth retardation, and hypotonia, and we identified an inherited 2 bp deletion causing a frameshift in BRPF1 (c.1052_1053del) in five affected family members. BRPF1 encodes a protein modifier of two histone acetyltransferases associated with ID: KAT6A (also known as MOZ or MYST3) and KAT6B (MORF or MYST4). The mRNA transcript was not significantly reduced in affected fibroblasts and most likely produces a truncated protein (p.Val351Glyfs8). The protein variant shows an aberrant cellular location, loss of certain protein interactions, and decreased histone H3K23 acetylation. We identified BRPF1 deletions or point mutations in six additional individuals with a similar phenotype. Deletions of the 3p25 region, containing BRPF1 and SETD5, cause a defined ID syndrome where most of the clinical features are attributed to SETD5 deficiency. We compared the clinical symptoms of individuals carrying mutations or small deletions of BRPF1 alone or SETD5 alone with those of individuals with deletions encompassing both BRPF1 and SETD5. We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency.

Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer

“…These cases are mainly from North America and Europe, where exome sequencing has been routinely used for clinical diagnosis of rare developmental disorders. As shown in table S1, most of the newly identified 12 individuals share key clinical features with those reported cases (12,33), including general developmental delay and gross/fine motor delay. Many showed intellectual disability and had language delay (table S1).…”

“…2), we then investigated the clinical relevance of these findings. We and others have reported 28 clinical cases of syndromic intellectual disability due to de novo or inherited BRPF1 variants (12,(33)(34)(35). We have now identified 12 previously unreported cases ( Fig.…”

“…We and others have just identified BRPF1 variants in 28 individuals with syndromic intellectual disability (12,(33)(34)(35)(36). The variants cause deficient H3K23 acetylation (12,33). This site is also propionylated (3), but the enzymes are elusive.…”

Lin‐Gettig syndrome: Craniosynostosis expands the spectrum of the KAT6B related disorders

“…Individuals with KAT6A mutations also demonstrate other clinical features that overlap with SBBYS and GPS (Table ) (Arboleda et al, ; Millan et al, ; Tham et al, ). BRPF1 , a regulator of both histone lysine acetyltransferases KAT6A and KAT6B , has also very recently been implicated in an intellectual disability syndrome with facial dysmorphisms like blepharophimosis that have similarity with KAT6B spectrum patients, although craniosynostosis has not yet been described (Mattioli et al, ; Yan et al, ).…”

Say‐Barber‐Biesecker‐Young‐Simpson syndrome and Genitopatellar syndrome: Lumping or splitting?

“…Very interestingly, Yan et al and Mattioli et al identified heterozygous sequence variants in the BRPF1 gene on chromosome 3p25, leading to a phenotype characterized by delayed psychomotor development, intellectual disability, delayed language, and dysmorphic facial features, most notably ptosis/blepharophimosis. Additional features may include poor growth, hypotonia, and seizures (intellectual developmental disorder with dysmorphic facies and ptosis, OMIM #617333).…”