X-linked mental retardation and severe short stature with a novel mutation of the <i>KDM5C</i> gene

Abstract

Many monogenetic disorders of short stature have autosomal recessive/dominant form of inheritance. However, X-linked short stature has not been well recognized. Herein, we report a case of a boy from a family with familial severe short stature and mental retardation, who displayed an X-linked recessive trait. The boy at the age of 4 yr and 6 mo presented with remarkable growth failure (height: 76.5 cm [-6.3 SD]) and mental retardation (IQ: 30) and cerebellar volume loss and without an external anomaly or microcephaly to our hospital. A careful interview to determine the family history suggested a genetic background of familial mental retardation and short stature. His mother had mild intellectual disability with normal stature and his maternal uncle had severe mental retardation with remarkably short stature. Whole-exome sequencing identified a pathogenic variant in the KDM5C gene, NM_004187: exon 23: c.3874_3875del: (p.Ala1292Glnfs*7). He presented with a novel frameshift mutation. His mother was a heterozygous carrier of the variant. This case suggests that a disorder associated with the KDM5C gene should be considered when patients present with remarkably short stature and X-linked mental retardation.

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

“…Unlike males hemizygous for pathogenic KDM5C variants, the clinical presentation of heterozygous females varies widely and is only now beginning to be characterized in detail. While up to 50% of females have no overt deficits, others show intellectual disability, developmental delay, learning and speech difficulties, hormonal imbalance, and anxiety [9,23,[26][27][28][29]. The basis for the incomplete penetrance of symptoms [26] ID…”

A Missense Variation in the KDM5C Gene Associated with X-Linked Intellectual Disability, Growth Failure, and Epilepsy

“…We presented a family of three brothers with X-linked intellectual disability caused by a missense variation (c.1602G > C, p.Trp534Cys) in the KDM5C gene for the first time in Korea. Previously reported patients with missense mutations in the KDM5C gene usually had mild to moderate intellectual impairment, short stature, and microcephaly [6]. However, all three male siblings in this report presented with severe intellectual disability, growth failure, and epilepsy.…”

“…KDM5C variation is inherited as an X-linked recessive trait and is associated with mild to severe intellectual disability. The clinical manifestations in affected males include intellectual disability, developmental delay, delayed speech and language development, autistic behavior, aggressive behavior, seizures, short stature, decreased body weight, microcephaly, progressive spastic paraplegia, lower limb hyperreflexia, and mild dysmorphic features [6]. These clinical features were first described as the Claes-Jensen type of X-linked intellectual development disorder (MIM #300534), and the current understanding of its genetic basis involves a central transcriptional repressive role for KDM5C.…”

“…The KDM5C gene, located at Xp11.22, encodes a histone demethylase that specifically targets di-and tri-methylated histone H3 lysine ece4 (H3K4me2 and H3K4me3) [7,8] and helps maintain the dynamic balance of the H3K4 methylation state [9]. The H3K4me2/3 substrates are associated with the promoters of transcriptionally active genes and play an essential role in gene transcription [6,7]. In mouse models, loss of KDM5C function caused defective development of the dendrites and dendritic spines, and these defects are often observed in human individuals with intellectual disabilities or autism spectrum disorder [7,10].…”

Novel Variations in the KDM5C Gene Causing X-Linked Intellectual Disability

“…To date, 57 pathogenic variations on the KDM5C gene have been described in the English literature. 9,14,15,18,[25][26][27][28][29][30][31][32][33][34][35][36] We summarized their loci and clinical manifestations in Figure 5. Of interest, the missense and splice site variations commonly occur in functional domains, and the nonsense and frameshift variations are frequently in nonfunctional regions.…”