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

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.Val351Glyfs*8). 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

Neuropathy target esterase impairments cause Oliver–McFarlane and Laurence–Moon syndromes

BackgroundOliver-McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence-Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause.MethodsWhole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines.ResultsEight mutations in six families with Oliver-McFarlane or Laurence-Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver-McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver-McFarlane and Laurence-Moon syndromes revealed extensive cerebellar degeneration and atrophy.ConclusionsPreviously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon-Holmes syndrome and Boucher-Neuhäuser syndromes. Discovery of these additional PNPLA6-opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance

Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility.

International audienceThe World Health Organization conservatively estimates that 80 million people suffer from infertility worldwide. Male factors are believed to be responsible for 20-50% of all infertility cases, but microdeletions of the Y chromosome are the only genetic defects altering human spermatogenesis that have been reported repeatedly. We focused our work on infertile men with a normal somatic karyotype but typical spermatozoa mainly characterized by large heads, a variable number of tails and an increased chromosomal content (OMIM 243060). We performed a genome-wide microsatellite scan on ten infertile men presenting this characteristic phenotype. In all of these men, we identified a common region of homozygosity harboring the aurora kinase C gene (AURKC) with a single nucleotide deletion in the AURKC coding sequence. In addition, we show that this founder mutation results in premature termination of translation, yielding a truncated protein that lacks the kinase domain. We conclude that the absence of AURKC causes male infertility owing to the production of large-headed multiflagellar polyploid spermatozoa

Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals

International audienc

DOORS syndrome and a recurrent truncating ATP6V1B2 variant

PURPOSE: Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [previously referred to as mental retardation], and seizures) syndrome. The aim of the study was to identify a genetic cause in families with DOORS syndrome and without a TBC1D24 variant. METHODS: Exome or Sanger sequencing was performed in individuals with a clinical diagnosis of DOORS syndrome without TBC1D24 variants. RESULTS: We identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. This variant was already reported in individuals with dominant deafness onychodystrophy (DDOD) syndrome. Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes. All families but one had developmental delay or intellectual disability and five individuals had epilepsy. We also describe two additional families with DDOD syndrome in whom the same variant was found. CONCLUSION: We expand the phenotype associated with ATP6V1B2 and propose another causal gene for DOORS syndrome. This finding suggests that DDOD and DOORS syndromes might lie on a spectrum of clinically and molecularly related conditions