Phenotypic characterization of KCTD3-related developmental epileptic encephalopathy.

The association between KCTD3 gene and neurogenetic disorders has only been published recently. In this report, we describe the clinical phenotype associated with 2 pathogenic variants in KCTD3 gene. Seven individuals (including one set of monozygotic twin) from 4 consanguineous families presented with developmental epileptic encephalopathy, global developmental delay, central hypotonia, progressive peripheral hypertonia, and variable dysmorphic facial features. Posterior fossa abnormalities (ranging from Dandy-Walker malformation to isolated hypoplasia of the cerebellar vermis) were consistently observed in addition to other variable neuroradiological abnormalities such as hydrocephalus and abnormal brain myelination. One patient also had a multicystic kidney. Whole exome sequencing revealed 2 probably pathogenic homozygous variants in KCTD3 gene that fully segregated with the disease. KCTD3 gene belongs to a family of accessory subunits that regulate the biophysical properties of ion channels, and is highly expressed in the kidney and brain. In this largest series to date on KCTD3-mutated patients, we show that biallelic loss of function mutations in KCTD3 lead to a consistent phenotype of developmental epileptic encephalopathy and abnormal cerebellum on brain imaging.

Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield.

Intellectual disability (ID) is a measurable phenotypic consequence of genetic and environmental factors. In this study, we prospectively assessed the diagnostic yield of genomic tools (molecular karyotyping, multi-gene panel and exome sequencing) in a cohort of 337 ID subjects as a first-tier test and compared it with a standard clinical evaluation performed in parallel. Standard clinical evaluation suggested a diagnosis in 16% of cases (54/337) but only 70% of these (38/54) were subsequently confirmed. On the other hand, the genomic approach revealed a likely diagnosis in 58% (n=196). These included copy number variants in 14% (n=54, 15% are novel), and point mutations revealed by multi-gene panel and exome sequencing in the remaining 43% (1% were found to have Fragile-X). The identified point mutations were mostly recessive (n=117, 81%), consistent with the high consanguinity of the study cohort, but also X-linked (n=8, 6%) and de novo dominant (n=19, 13%). When applied directly on all cases with negative molecular karyotyping, the diagnostic yield of exome sequencing was 60% (77/129). Exome sequencing also identified likely pathogenic variants in three novel candidate genes (DENND5A, NEMF and DNHD1) each of which harbored independent homozygous mutations in patients with overlapping phenotypes. In addition, exome sequencing revealed de novo and recessive variants in 32 genes (MAMDC2, TUBAL3, CPNE6, KLHL24, USP2, PIP5K1A, UBE4A, TP53TG5, ATOH1, C16ORF90, SLC39A14, TRERF1, RGL1, CDH11, SYDE2, HIRA, FEZF2, PROCA1, PIANP, PLK2, QRFPR, AP3B2, NUDT2, UFC1, BTN3A2, TADA1, ARFGEF3, FAM160B1, ZMYM5, SLC45A1, ARHGAP33 and CAPS2), which we highlight as potential candidates on the basis of several lines of evidence, and one of these genes (SLC39A14) was biallelically inactivated in a potentially treatable form of hypermanganesemia and neurodegeneration. Finally, likely causal variants in previously published candidate genes were identified (ASTN1, HELZ, THOC6, WDR45B, ADRA2B and CLIP1), thus supporting their involvement in ID pathogenesis. Our results expand the morbid genome of ID and support the adoption of genomics as a first-tier test for individuals with ID.