Expanding the Phenotypic Spectrum of KMT5B-associated Syndromic Intellectual Disability

Background: Neurodevelopmental disorders are a wide and heterozygous group of conditions, many of which caused by monogenic etiologies. Recently, deleterious variants in KMT5B were implicated in 11 individuals with intellectual disability (ID).

Patients and Methods: We describe two unrelated patients with global developmental delay (GDD), ID and macrocephaly.

Patient A, the first child born to nonconsanguineous healthy parents of mixed-Jewish descent, presented at the age of 12 months for evaluation due to GDD: raised his head at 5.5 months, rolled over at 7 months and began crawling at 9 months of age. Physical features included macrocephaly, strabismus, broad forehead, short neck and mild hypertelorism. Brain MRI and EEG were normal.

Patient B, first child born to healthy nonconsanguineous parents of Ashkenazi-Jewish descent, presented at the age of 2.5 years due to profound GDD. During infancy, brain ultrasound was performed due to large head circumference, and was considered normal. He also had astigmatism and hypermetropia, broad forehead, conical fingers, hypotonia and joint hypermobility.

Chromosomal microarray analysis (CMA) and molecular analysis for Fragile X syndrome, were normal for both probands, as was Sanger sequencing for PTEN in Patient 2.

Whole exome sequencing (WES) was pursued for the probands and their parents, via a governmentally-funded pilot program.

Results: Trio-WES revealed a distinct, previously unreported de-novo heterozygous pathogenic variant in the KMT5B gene in each proband: c.541C>G, p.H181D in Patient 1, and c.764A>T, p.N255I in Patient 2.

Conclusion: Our findings expand the current knowledge regarding the phenotype and mutation spectrum of KMT5B-associated ID.