Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum

Abstract

Background: Pathogenic variants of the lysine acetyltransferase 6A or KAT6A gene are associated with a newly identified neurodevelopmental disorder characterized mainly by intellectual disability of variable severity and speech delay, hypotonia, and heart and eye malformations. Although loss of function (LoF) mutations were initially reported as causing this disorder, missense mutations, to date always involving serine residues, have recently been associated with a form of the disorder without cardiac involvement.Results: In this study we present five new patients, four with truncating mutations and one with a missense change and the only one not presenting with cardiac anomalies. The missense change [p.(Gly359Ser)], also predicted to affect splicing by in silico tools, was functionally tested in the patient's lymphocyte RNA revealing a splicing effect for this allele that would lead to a frameshift and premature truncation.Conclusions: An extensive revision of the clinical features of these five patients revealed high concordance with the 80 cases previously reported, including developmental delay with speech delay, feeding difficulties, hypotonia, a high bulbous nose, and recurrent infections. Other features present in some of these five patients, such as cryptorchidism in males, syndactyly, and trigonocephaly, expand the clinical spectrum of this syndrome.

Identification of a novel KAT6A variant in an infant presenting with facial dysmorphism and developmental delay: a case report and literature review

“…Since a recurrent translocation was noted in acute monocytic leukemia [ 19 ], pathogenic variants and misregulation of the human KAT6A gene have been identified in solid tumors and patients with syndromic disease with developmental disorders of variable severity [ 1 , 2 , 18 , 20 ]. As WES has become a powerful means of investigating de novo pathogenic variants in neurodevelopmental disorders, the number of patients identified with novel genetic KAT6A variants has gradually increased [ 5 , 7 , 8 , 13 , 21 , 22 ].…”

“…The major features of this syndrome include developmental delay, facial dysmorphism, microcephaly, cardiac anomalies, and gastrointestinal problems [ 5 ]. The frequent dysmorphic facial appearances in ARTHS include a prominent nasal bridge with a broad nasal tip, a thin-tented upper lip, and low-set ears [ 5 , 7 ]. Most patients with pathogenic KAT6A variants have intellectual disabilities and speech delays that range from mild to severe.…”

“…Most patients with pathogenic KAT6A variants have intellectual disabilities and speech delays that range from mild to severe. The genotype–phenotype analysis demonstrated that the truncating frameshift or nonsense variant within the penultimate and ultimate exons (16 and 17, respectively) is associated with severe developmental delay [ 5 , 7 , 13 ].…”

De Novo PORCN and ZIC2 Mutations in a Highly Consanguineous Family

“…When presented with highly consanguineous families segregating a disease phenotype, one of the first approaches is to search for pathogenic mutations in homozygosity tracks. In addition, performing WES analysis only on the index case is a common practice, which, in highly consanguineous populations, yields acceptable diagnostic results [ 30 ]. While the cost advantage of such an approach is evident, it is important to keep in mind that, even in cases with a very high consanguinity, de novo disease causing mutations may still be present, representing up to 27.8% of the ID mutations identified in these families [ 29 ] when trio-WES is performed.…”

A de novo heterozygous variant in KAT6A is associated with a newly named neurodevelopmental disorder Arboleda-Tham syndrome—a case report

“…The KAT6A gene, codes for one member of the histone acetyltransferase (HAT) family MYST. Collectively, HAT and histone deacetylase (HDAC) enzymes play key roles in essential cellular processes including the cell cycle, metabolism, apoptosis, and stem cell maintenance through remodeling chromatin (3,4). The transcription factors Runx1 and Runx2 are directly regulated by the KAT6A gene by its serine-and methionine-rich domain (5,6).…”