Novel truncating variants expand the phenotypic spectrum of KAT6B-related disorders.

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and Genitopatellar syndrome (GTPTS) are very rare conditions caused by KAT6B truncating variants. Because of both syndromes often share common features the associated phenotypes are usually grouped under the term "KAT6B-related disorders." However, particular signs of each syndrome have been reported and their appearance seems to be dependent on where the KAT6B variant is located. Thus, whereas truncating variants associated with SBBYSS have their highest density in the distal part of exon 18, those resulting in GTPTS are distributed between the end of exon 17 and beginning of exon 18. Here, we reported two de novo heterozygous KAT6B truncating variants. The first variant (c.5802delA; p.A1935Pfs*16), identified in a boy with SSBYSS phenotype, resulting in the most distal KAT6B truncating variant reported up-to-date in the scientific literature. The second variant (c.3152delG; p.S1051Tfs*63), located in a region hitherto defined as specific of SBBYSS, seems to cause an overlapping SBBYSS/GTPTS phenotype. The clinical and genetic characterization of these patients could contribute to the understanding of the KAT6B-related disorders.

A novel truncating variant within exon 7 of KAT6B associated with features of both Say-Barber-Bieseker-Young-Simpson syndrome and genitopatellar syndrome: Further evidence of a continuum in the clinical spectrum of KAT6B-related disorders.

KAT6B sequence variants have been identified in both patients with the Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and in the genitopatellar syndrome (GPS). In SBBYSS, they were reported to affect mostly exons 16-18 of KAT6B, and the predicted mechanism of pathogenesis was haploinsufficiency or a partial loss of protein function. Truncating variants in KAT6B leading to GPS appear to cluster within the proximal portion of exon 18, associated with a dominant-negative effect of the mutated protein, most likely. Although SBBYSS and GPS have been initially considered allelic disorders with distinctive genetic and clinical features, there is evidence that they represent two ends of a spectrum of conditions referable as KAT6B-related disorders. We detected a de novo truncating variant within exon 7 of KAT6B in a 8-year-old female who presented with mild intellectual disability, facial dysmorphisms highly consistent with SBBYSS, and skeletal anomalies including exostosis, that are usually considered component manifestations of GPS. Following the clinical diagnosis driven by the striking facial phenotype, we analyzed the KAT6B gene by NGS techniques. The present report highlights the pivotal role of clinical genetics in avoiding clear-cut genotype-phenotype categories in syndromic forms of intellectual disability. In addition, it further supports the evidence that a continuum exists within the clinical spectrum of KAT6B-associated disorders.

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

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and genitopatellar syndrome (GTPTS) are clinically similar disorders with some overlapping features. Although they are currently considered to be distinct clinical entities, both were found to be caused by de novo truncating sequence variants in the KAT6B (lysine acetyltransferase 6B) gene, strongly suggesting that they are allelic disorders. Herein, we report the clinical and genetic findings in a girl presenting with a serious multiple congenital anomaly syndrome with phenotypic features overlapping both SBBYSS and GTPTS; pointing out that the clinical distinction between these disorders is not exact and there do exist patients, in whom conventional clinical classification is problematic. Genetic analyses revealed a truncating c.4592delA (p.Asn1531Thrfs*18) variant in the last KAT6B exon. Our findings support that phenotypes associated with typical KAT6B disease-causing variants should be referred to as 'KAT6B spectrum disorders' or 'KAT6B related disorders', rather than their current SBBYSS and GTPTS classification.

Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms.

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders.