De Novo Mutation in KMT2C Manifesting as Kleefstra Syndrome 2: Case Report and Literature Review

Abstract

Diagnosis of pediatric intellectual disability (ID) can be difficult because it is due to a vast number of established and novel causes. Here, we described a full-term female infant affected by Kleefstra syndrome-2 presenting with neurodevelopmental disorder, a history of hypotonia and minor face anomalies. A systematic literature review was also performed. The patient was a 6-year-old Caucasian female. In the family history there was no intellectual disability or genetic conditions. Auxological parameters at birth were adequate for gestational age. Clinical evaluation at 6 months revealed hypotonia and, successively, delay in the acquisition of the stages of psychomotor development. Auditory, visual, somatosensory, and motor-evoked potentials were normal. A brain MRI, performed at 9 months, showed minimal gliotic changes in bilateral occipital periventricular white matter. Neuropsychiatric control, performed at 5 years, established a definitive diagnosis of childhood autism and developmental delay. Molecular analysis of the exome revealed a novel KMT2C missense variant: c.9244C > T (p.Pro3082Ser) at a heterozygous state, giving her a diagnosis of Kleefstra syndrome 2. Parents did not show the variant. Literature review (four retrieved eligible studies, 10 patients) showed that all individuals had mild, moderate, or severe ID; language and motor delay; and autism. Short stature, microcephaly, childhood hypotonia and plagiocephaly were also present. Conclusion. Kleefstra syndrome 2 is a difficult diagnosis of a rare condition with a high clinical phenotypic heterogeneity. This study suggests that it must be taken in account in the work-up of an orphan diagnosis of intellectual disability and/or autism spectrum disorder.

Precise definition of the breakpoints of an apparently balanced translocation between chromosome 3q26 and chromosome 7q36: Role of KMT2C disruption

“…Phenotypic comparisons between this patient and previously reported patient with KMT2C pathogenic variants showed variability in the physical characteristics, but intellectual disability was inevitable to varying degrees and autistic symptoms were frequent (Table S1). 2,4–7 In view of these rather nonspecific dysmorphic features of Kleefstra syndrome 2, as reviewed in this study, the contribution of KMT2C disruption would never have been confirmed on clinical grounds alone without the genomic analysis.…”

A novel 11 base pair deletion in KMT2C resulting in Kleefstra syndrome 2

“…Only two non‐truncating mutations in KMT2C resulting in Kleefstra syndrome 2 have been described (Cheema et al., 2022; Siano et al., 2022). A missense variant (NM_170606.2: c.9294C>T, p.Pro3082Ser) and a three amino acid in‐frame deletion (NM_170606.2: c.7247_7258del, p.His2416_Pro2419del), both impact protein regions outside of any known functional domains (Figure 2) and are both N‐terminal of the SET domain.…”

“…They subsequently coined the condition, Kleefstra syndrome 2 (MIM: 617768). Fourteen other cases have subsequently been described, resulting from haploinsufficiency of KMT2C (Brunet et al, 2021;Cheema et al, 2022;Faundes et al, 2018;Koemans et al, 2017;Schoch et al, 2020;Siano et al, 2022;Wu & Li, 2022).…”

KMT2C knockout generates ASD-like behaviors in mice

“…Using fruit flies it has been shown that KMT2C binds to promoter regions of genes involved in neuronal processes, and its loss of function produce severe deficits in memory formation (Koemans et al, 2017). In humans, mutations in KMT2C have been found in individuals with intellectual disabilities including Kleefstra syndrome 2 and ASD (Iossifov et al, 2012;Stessman et al, 2017;Lavery et al, 2020;Satterstrom et al, 2020;Dhaliwal et al, 2021;Siano et al, 2022;Tuncay et al, 2022;Zhou et al, 2022). Interestingly only eleven patients have been described with mutations in KMT2C (Siano et al, 2022), with only one long term report showing long lasting phenotypes (Wu and Li, 2022).…”

“…In humans, mutations in KMT2C have been found in individuals with intellectual disabilities including Kleefstra syndrome 2 and ASD (Iossifov et al, 2012;Stessman et al, 2017;Lavery et al, 2020;Satterstrom et al, 2020;Dhaliwal et al, 2021;Siano et al, 2022;Tuncay et al, 2022;Zhou et al, 2022). Interestingly only eleven patients have been described with mutations in KMT2C (Siano et al, 2022), with only one long term report showing long lasting phenotypes (Wu and Li, 2022). Thus, phenotypes associated to KMT2C mutants have not been fully characterized.…”