De novo loss of function mutations in KIAA2022 are associated with epilepsy and neurodevelopmental delay in females

Abstract

Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, X‐linked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of loss‐of‐function KIAA2022 mutations have been described previously in 15 males, born from unaffected carrier mothers, but few females. Using whole‐exome sequencing, we identified a cohort of five unrelated female patients with de novo probably gene damaging variants in KIAA2022 and core phenotypic features of ID, developmental delay, epilepsy refractory to treatment, and impaired language, of similar severity as reported for male counterparts. This study supports KIAA2022 as a novel cause of X‐linked dominant ID, and broadens the phenotype for KIAA2022 mutations.

Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders

“…These genes could be considered critical in the evaluation of individuals with epilepsy and NDD. Of note, the rate of gene discovery for genetic epilepsies has been significant in recent years and additional potentially high‐yield genes have been reported recently (ie, DEPDC5, KCNT1, IQSEC2, KIAA2022 , and SLC6A1 ) . Based on our results and limited published evidence, the CACNB4, EFHC1, SRPX2 , and ATP6AP2 genes appear to be low‐yield and variants in these genes should be reviewed cautiously.…”

“…Of note, the rate of gene discovery for genetic epilepsies has been significant in recent years and additional potentially high-yield genes have been reported recently (ie, DEPDC5, KCNT1, IQSEC2, KIAA2022, and SLC6A1). [29][30][31] Based on our results and limited published evidence, the CACNB4, EFHC1, SRPX2, and ATP6AP2 genes appear to be lowyield and variants in these genes should be reviewed cautiously. When variants are identified in a proband, parental testing should be considered to clarify the clinical significance of the variant and determine recurrence risk for the family.…”

Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with KIAA2022 pathogenic variants and review of the literature

“…The pathogenic variant found in Patient 1, c.652C > T(p.Arg218*), was previously reported in a female patient described by de Lange et al () and Webster et al (). When comparing our patient to the female patient, the two share some of the same features including hypotonia, a broad‐based gait, and postnatal growth retardation.…”

“…Recently, Charzewska et al () reported a family with two patients with whole gene duplication spanning a 384‐kb segment, but interestingly with decreased expression of KIAA2022 protein in fibroblasts and lymphocytes. A recent paper described five females with de novo pathogenic variants in KIAA2022 , most of them described as nondysmorphic and with mild to severe intellectual disability (Webster et al, ). Skewed X‐inactivation in the brain was presented as the possible explanation for the differences.…”

“…KIAA2022 is an X‐linked gene that has been implicated in X‐linked intellectual disability (XLID) (Athanasakis et al, ; Cantagrel et al, ; de Lange et al, ; Farach & Northrup, ; Kuroda et al, ; Moysés‐Oliveira et al, ; Van Maldergem et al, ; Webster et al, ). Pathogenic variants in X chromosome genes are believed to account for 5–10% of intellectual disabilities (ID) in males, and to date over 100 XLID genes have been discovered (Lubs, Stevenson, & Schwartz, ).…”