Diagnosis of Arboleda-Tham syndrome by whole-exome sequencing in an Asian girl with severe developmental delay

Abstract

Objective: This study aims to report a severe phenotype of Arboleda-Tham syndrome in a 20-month-old girl, characterized by global developmental delay, distinct facial features, intellectual disability. Arboleda-Tham syndrome is known for its wide phenotypic spectrum and is associated with truncating variants in the KAT6A gene.

Methods: To diagnose this case, a combination of clinical phenotype assessment and whole-exome sequencing technology was employed. The genetic analysis involved whole-exome sequencing, followed by confirmation of the identified variant through Sanger sequencing.

Results: The whole-exome sequencing revealed a novel de novo frameshift mutation c.3048del (p.Leu1017Serfs*17) in the KAT6A gene, which is classified as likely pathogenic. This mutation was not found in the ClinVar and HGMD databases and was not present in her parents. The mutation leads to protein truncation or activation of nonsense-mediated mRNA degradation. The mutation is located within exon 16, potentially leading to protein truncation or activation of nonsense-mediated mRNA degradation. Protein modeling suggested that the de novo KAT6A mutation might alter hydrogen bonding and reduce protein stability, potentially damaging the protein structure and function.

Conclusion: This study expands the understanding of the genetic basis of Arboleda-Tham syndrome, highlighting the importance of whole-exome sequencing in diagnosing cases with varied clinical presentations. The discovery of the novel KAT6A mutation adds to the spectrum of known pathogenic variants and underscores the significance of this gene in the syndrome's pathology.

Keywords: Arboleda‐Tham syndrome; KAT6A; de novo truncating variants; facial dysmorphism; global developmental delay.

FIGURE 1

Pedigree verification and the heterozygous mutation c.3048del(p.Leu1017Serfs*17) in the KAT6A gene of the proband.

FIGURE 2

(a) Three‐dimensional structure of wild‐type (left) and mutant (right) the KAT6A and hydrogen bond changes in the variants and prediction of protein stability changes upon single point mutation (DDG, Kcal/mol) (down). The changes in the protein stability were evaluated by DDG (the free energy change value, Kcal/mol). Negative DDG value indicates that the mutant protein possesses poor stability and vice versa. (b) The results of multiple amino acid alignments of KAT6A orthologues in the UCSC database. The red arrow mark presents p.Leu1017Serfs*17.

FIGURE 3

Spectrum of (likely) pathogenic KAT6A mutations in the studied cohort of 134 unrelated individuals, derived from the previously reported variants and novel variant reported in our study (purple font and outline). Color‐coded domains include Ser/Met domain (red font and outline): serine and methionine‐rich transactivation domain (1414–2004), ACIDIC domain (green font and outline): acidic glutamate/aspartate‐rich domain (788–1414), HAT domain (orange font and outline): histone‐acetyltransferase domain (AA 314–787), double PHD domains (blue font and outline): double‐plant homeodomain finger (207–313), and NEMM (black font and outline): nuclear localization domain (1–206).