A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants

Abstract

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals' family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants.

Keywords: KDM5; epigenetics; genetic syndromes; histone demethylation; intellectual disabilities; neurodevelopmental disorders; polygenetic interactions.

Figure 1

Dominant and bi-allelic KDM5B variants from this cohort and the literature represented within the KDM5B protein. The active regions are named and highlighted in different colors according to the legend. Variant types are also indicated, and if the same one was shared by multiple individuals, it is shown as a circle with the total number. Illustration is adapted from https://proteinpaint.stjude.org/.

Figure 2

Photographs of individuals with KDM5B variants. (A) Individual No. 5 (p.Ala804Val) at the age of 10 years old. Note the macrotia, straight eyebrows, telecanthus, the full nasal tip, and the broad mouth. (B) Individual No. 19 (Whole gene deletion) at the age of 18 years old. Note the brachycephaly, elongated face, high forehead, temporally sparse hair, broad eyebrows, bilaterally temporal narrowing, downslanted palpebral fissures, short philtrum, facial asymmetry (left side is slightly shorter), increased cervical length and width, and large hands with long, tapered fingers. (C) Individual No. 21 (p.Glu2Ter and p.Trp387Ter) at the age of 4 years old. Note the broad forehead, the midface retraction, the full nasal tip, and the micrognathia.