Caregiver‐reported characteristics of children diagnosed with pathogenic variants in KDM5C

Abstract

Loss of function variants in the lysine demethylase 5C (KDM5C) gene account for approximately 0.7-2.8% of X-linked intellectual disability (ID) cases and pose significant burdens for patients and their caregivers. To date, 45 unique variants in KDM5C have been reported in individuals with ID. As a rare disorder, its etiology and natural history remain an area of active investigation, with treatment limited to symptom management. Previous studies have found that males present with moderate to severe ID with significant syndromic comorbidities such as epilepsy, short stature, and craniofacial abnormalities. Although not as well characterized, females have been reported to predominantly display mild to moderate ID with approximately half being asymptomatic. Here, we present caregiver-reported data for 37 unrelated individuals with pathogenic variants in KDM5C; the largest cohort reported to-date. We find that up to 70% of affected females were reported to display syndromic features including gastrointestinal dysfunction and hearing impairment. Additionally, more than half of individuals reported a diagnosis of autism spectrum disorder or described features consistent with this spectrum. Our data thus provide further evidence of sexually dimorphic heterogeneity in disease presentation and suggest that pathogenic variants in KDM5C may be more common than previously assumed.

Expanding the Spectrum of KDM5C Neurodevelopmental Disorder: A Novel De Novo Stop Variant in a Young Woman and Emerging Genotype–Phenotype Correlations

“…Additionally, behavioral issues such as aggressive behavior, low frustration tolerance, anxiety, and social disability are often reported in young women, such as our patient. Our observations are in line with a recent caregiver report on the characteristics of patients diagnosed with KDM5C variants [ 1 ]: all females had developmental delay and language impairment, 60% had intellectual disability, 70% had short stature, 56% had aggressive behavior, and 44% had anxiety disorder. The clinical geneticist should be aware of these specific clinical features, especially when attempting the interpretation of more variants emerging from WES analysis [ 22 ].…”

“…Claes–Jensen type (OMIM#300534), an X-linked syndromic neurodevelopmental disorder, is caused by mutations in the KDM5C gene (OMIM*314690). Maternally transmitted or, more rarely, de novo pathogenic variants explain about 0.7–2.8% of X-linked intellectual disability [ 1 ]. KDM5C encodes a histone demethylase that specifically acts on lysine 4 of histone H3 (H3K4), regulating transcriptional repression and chromatin remodeling.…”

Molecular and cellular events linking variants in the histone demethylase KDM5C to the intellectual disability disorder Claes‐Jensen syndrome

“…1A; Table 1). We will refer to this disorder as Claes-Jensen syndrome, although it should be noted that it has also been referred to as CJ-XLID, MRXSCJ, and KDM5C-RD [7][8][9][10].…”

A female case with novel KDM5C heterozygous variation presenting with Claes-Jensen type-like phonotype

“…In a recent cohort study, approximately 70% of females heterozygous for pathogenic KDM5C variants were symptomatic, higher than 52% in another study [1,7]. To date, all females with de novo mutation in the KDM5C gene have presented with symptomatic features [1].…”

“…KDM5C dysfunction causes X-linked intellectual disability in males (intellectual developmental disorder, X-linked, syndromic, Claes-Jensen type; MIM# 300,534), and is characterized by moderate-to-severe intellectual disability, short stature, dysmorphic features, seizures, and spasticity [3][4][5]. Most individuals with KDM5C variants are males; however, carrier females with milder phenotypes including intellectual disability and spasticity, have also been documented [1,6,7].…”