ヤング・シンプソン症候群

INTRODUCTION: 46,XY differences of sex development (DSD) are conditions with extreme phenotypic and genetic heterogeneity. Therefore, their diagnosis remains a major challenge for both clinicians and geneticists. In this study, we aimed to identify the underlying genetic causes of DSD in a series of 3 Moroccan patients with syndromic 46,XY DSD recruited in the BRO Biobank. CASE PRESENTATIONS: Methods: Karyotyping analysis was performed on peripheral blood samples using standard R banding techniques. SRY gene was analyzed using PCR amplification followed by Sanger sequencing. Whole exome sequencing (WES) was performed after unsuccessful conventional genetic analyses. Candidate variants were evaluated by segregation analysis and molecular modeling. RESULTS: WES identified three pathogenic variants in genes encoding various components of the epigenetic machinery: in patient 1, a novel heterozygous frameshift variant c.4072dup (p.Glu1358GlyfsTer29) in the KAT6B gene associated with two clinically distinct syndromes (genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome) was detected; in patient 2, we identified a previously reported de novo heterozygous nonsense variant c.12943C>T (p.Gln4315Ter) in KMT2D responsible for Kabuki syndrome; in patient 3, WES revealed a novel heterozygous missense variant c.4056C>G (p.Phe1352Leu) in CHD7 responsible for CHARGE syndrome. We discuss the genotype-phenotype correlation in these syndromic 46,XY DSD and discuss the relevance of the epigenetic genes in sexual development. CONCLUSION: Our findings highlight the utility of WES in discriminating clinically overlapping syndromic 46,XY DSD to provide an accurate diagnosis, thus allowing better follow-up and appropriate patient management. In addition, our study enriched the mutational spectrum of syndromic 46,XY DSD and confirmed the genotype-phenotype correlations.

Pathogenic variants in KAT6B (Lysine acetyltransferase 6B) are associated with two clinically overlapping autosomal dominant disorders Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736), and Genitopatellar syndrome (GPS) (OMIM 606170). More recently, the clinical spectrum of KAT6B disorders has expanded and KAT6B disorders have been suggested to consist of a spectrum of disorders with intermediate and overlapping clinical manifestations. Pathogenic variants in KAT6B mainly occur de novo, with only 3 reports of inherited variants. Here, we describe clinical and molecular findings in a three-generation Danish family with a segregating, previously unreported, pathogenic KAT6B variant. The variant is associated with a phenotype not otherwise specified (neither SBBYSS nor GPS) and with variable expressivity, adding further evidence that KAT6B disorders should be seen as a broad clinical spectrum. Furthermore, we highlight the existence of intra-familial variability and that pathogenic variants in KAT6B can be inherited from mildly affected parents.

Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson Syndrome (SBBYSS) are clinically distinct neurodevelopmental disorders caused by monoallelic pathogenic variants in KAT6B. In some cases, GPS and SBBYSS features can overlap, determining an intermediate phenotype. In the present study, we describe seven patients, four with a clinical diagnosis of SBBYSS and three presenting with an intermediate phenotype. All patients carried de novo pathogenic variants in KAT6B that were identified by exome sequencing. Five variants were novel. We provide both molecular and clinical findings, highlighting the previously undescribed association with two additional features: partial penoscrotal transposition and hypopigmented macules. We performed a review of the literature, listing the clinical features of 152 patients described in 33 papers, with a molecularly confirmed diagnosis of KAT6B-related disorders, reporting the frequency of each clinical feature detected in patients diagnosed with SBBYSS and GPS. The present work provides new insights into the phenotype associated with "KAT6B-related disorders", expanding the spectrum of features that can lead to a clinical suspicion of these conditions, also guiding the molecular investigations.

KAT6B mutations are responsible for Say-Barber-Biesecker-Young-Simpson syndrome or Genitopatellar syndrome, with most mutations occurring in its exon 18. A pregnancy with normal early antenatal examination revealed the presence of hypospadias in the fetus but with no abnormal amniotic fluid volume in ultrasonography at 29th+ 4d weeks' gestation. After amniocentesis, the trios' whole exome sequencing was performed and a novel frameshift mutation (KAT6B: exon10: c.2153_2159del, p. R718Lfs*3) was identified for her fetus, then verified by the parents as a de novo mutation. Following this couple's decision to induce labor, the appearance of the fetus had hypospadias but with a normal face and was able to be palpated for the patella. KAT6B mutations often occur with a variety of symptoms. To our acknowledgment, this is the first report of a novel de novo KAT6B mutation causing only hypospadias for the fetus, which further expands the spectrum of KAT6B variants and the genotype-phenotype relationship for this disease.

Loss of the gene encoding the histone acetyltransferase KAT6B (MYST4/MORF/QKF) causes developmental brain abnormalities as well as behavioral and cognitive defects in mice. In humans, heterozygous variants in the KAT6B gene cause two cognitive disorders, Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS; OMIM:603736) and genitopatellar syndrome (GTPTS; OMIM:606170). Although the effects of KAT6B homozygous and heterozygous mutations have been documented in humans and mice, KAT6B gain-of-function effects have not been reported. Here, we show that overexpression of the Kat6b gene in mice caused aggression, anxiety, and spontaneous epilepsy. Kat6b overexpression led to an increase in histone H3 lysine 9 acetylation and upregulation of genes driving nervous system development and neuronal differentiation. Kat6b overexpression additionally promoted neural stem cell proliferation and favored neuronal over astrocyte differentiation in vivo and in vitro. Our results suggest that, in addition to loss-of-function alleles, gain-of-function KAT6B alleles may be detrimental for brain development.