The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome sequencing and copy number study

Abstract

Early-onset epileptic encephalopathy (EE) and combined developmental and epileptic encephalopathies (DEE) are clinically and genetically heterogeneous severely devastating conditions. Recent studies emphasized de novo variants as major underlying cause suggesting a generally low-recurrence risk. In order to better understand the full genetic landscape of EE and DEE, we performed high-resolution chromosomal microarray analysis in combination with whole-exome sequencing in 63 deeply phenotyped independent patients. After bioinformatic filtering for rare variants, diagnostic yield was improved for recessive disorders by manual data curation as well as molecular modeling of missense variants and untargeted plasma-metabolomics in selected patients. In total, we yielded a diagnosis in ∼42% of cases with causative copy number variants in 6 patients (∼10%) and causative sequence variants in 16 established disease genes in 20 patients (∼32%), including compound heterozygosity for causative sequence and copy number variants in one patient. In total, 38% of diagnosed cases were caused by recessive genes, of which two cases escaped automatic calling due to one allele occurring de novo. Notably, we found the recessive gene SPATA5 causative in as much as 3% of our cohort, indicating that it may have been underdiagnosed in previous studies. We further support candidacy for neurodevelopmental disorders of four previously described genes ( PIK3AP1 , GTF3C3, UFC1 , and WRAP53 ), three of which also followed a recessive inheritance pattern. Our results therefore confirm the importance of de novo causative gene variants in EE/DEE, but additionally illustrate the major role of mostly compound heterozygous or hemizygous recessive inheritance and consequently high-recurrence risk.

A scoping review and proposed workflow for multi-omic rare disease research

“…A further 19 articles were identified from additional sources, not included in the initial search numbers. This included five articles which were full text versions of conference abstracts [38][39][40][41][42]. One paper returned in the initial search published through TCGA [43], led to the identification of a further 13 articles on multi-omics of rare cancers [44][45][46][47][48][49][50][51][52][53][54][55][56].…”

“…3). Two of the final 66 included papers were published in 2019, despite the 2018 date restriction, as these were identified from within the additional TCGA search [38,59]. Evolution of inclusion and exclusion criteria is not unusual within the process of conducting scoping reviews [37].…”

“…Congenital absence of the ACL v / PCL w • Identification of genomic, proteomic, transcriptomic and metabolomic mutations [38,[130][131][132]. • Diagnosis of mitochondrial aconitase deficiency [58].…”

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform specific start-loss mutations of essential genes can cause genetic diseases

“…Mostly, dominant acting, de novo mutations have been identified in children suffering from DEEs 3 , and only a limited number of genes with a recessive mode of inheritance are known so far, with a higher occurrence rate in consanguineous populations 4 . A recent cohort study on DEEs employing whole exome sequencing (WES) and copy-number analysis, however, found that up to 38% of diagnosed cases might be caused by recessive genes, indicating that the importance of this mode of inheritance in DEEs has been underestimated 5 .…”

Biallelic CACNA2D2 variants in epileptic encephalopathy and cerebellar atrophy

“…A substantial number of DEE patients have been shown to have an underlying genetic etiology, with de novo heterozygous variants playing an important role . With rapid advancements in molecular biology and genetic techniques, >100 genes have been associated with DEEs in the last 20 years, revolutionizing our understanding of their molecular etiology .…”