Homozygous missense variants in CACNB4 underlie autosomal recessive epilepsy in two unrelated Pakistani consanguineous families.

A novel mutation in SETD1A is associated with early-onset epilepsy—a rare case report

This study may expand the mutation and phenotypic spectrum of SETD1A-related disorders, establishing the relationship between SETD1A variants and isolated early-onset epilepsy without accompanying severe neurodevelopmental deficits, and highlighting the value of genetic testing in infants with unexplained epilepsy.

Biallelic variants in consanguineous families causing neurodevelopmental disorders

Aim: Identify new genetic variants linked to neurodevelopmental disorders to be used in routine genetic diagnostics. Methods: Whole exome sequencing (WES) was used for ten unrelated families from Jordan characterized by one or two affected members with neurodevelopmental disorders (NDDs), in which the parents are consanguineous in nine families. Results: Ten variants are identified in this study; one variant per family. Eight variants are identified by cross-link with the pathogenic variants in ClinVar and in our in-house database, and two variants are identified for the first time. Nine of the total identified variants are homozygous in the nine consanguineous families and one variant is heterozygous in the non-consanguineous family. Three of the identified variants were previously reported in unrelated Jordanian families compared to the families in this study. These three variants are NM_018359.5:c.344T>A;p.Val115Glu in the gene UFSP2, NM_000487.6:c.256C>G;p.Arg86Gly in the gene ARSA and NM_017882.3:c.144G>A;p.Trp48* in the gene CLN6. The variants that are identified for the first time are splicing variants; splice donor variant NM_000433.4:c.366+1G>C in the gene NCF2 and splice acceptor variant NM_000191.3:c.498-1G>A in the gene HMGCL. Conclusions: The results of this study stress the importance of continuous research using WES for NDDs in Jordan to identify new variants.

Identification of biallelic loss-of-function PREP variants in three individuals with syndromic intellectual disability

Background Neurodevelopmental disorders are one of the most prevalent reasons for genetic testing in childhood. Despite the identification of over 1950 associated genes, many proposed candidate genes lack convincing gene-disease validity. The gene PREP encodes the broadly expressed prolyl endopeptidase whose exact function remains largely unknown. A homozygous PREP variant has been reported once as a candidate gene in two siblings with intellectual disability but no functional studies were conducted. Methods Exome and trio genome sequencing were performed in two unrelated families as part of larger cohorts. Segregation analysis, RNA sequencing and immunoblots were performed to further examine the pathogenicity of detected PREP variants. Results We report three individuals from two unrelated families who presented with intellectual disability, behavioural abnormalities, strabismus, generalised muscular hypotonia, dysmorphic facial features and epilepsy. Exome and genome sequencing identified two different homozygous rare PREP variants: c.1570_1573dup, p.(Asn525Thrfs*5) and c.1839-2A>G, p.?. RNA sequencing confirmed the detected intronic variant to result in two aberrant mRNA isoforms. In patient-derived cells immunoblots showed absence of PREP protein. Conclusion Our data suggest PREP deficiency as the underlying cause of a syndromic neurodevelopmental disorder.

[Analysis of KCNA2 gene variant in a Chinese pedigree affected with developmental and epileptic encephalopathy].

Oligogenic inheritance in epilepsy: A systematic exome-wide analysis.

OBJECTIVE Genetic factors contribute to the majority of epilepsies, but the exact genetic cause remains unknown in most patients. Incomplete penetrance and variable expressivity are frequent, and recent studies showed a burden of deleterious variants in epilepsy genes, suggesting a role for oligogenic inheritance. Here, we investigated both monogenic and oligogenic inheritance in a large cohort of patients with epilepsy. METHODS We used exome data of 422 patients and 5308 nonepileptic individuals generated by the Epi25 Collaborative project. First, a stepwise monogenic analysis was performed on all patients. Next, we restricted the cases and controls to samples sequenced with the same capture kit and removed ancestry outliers using a principal component analysis approach. We performed an oligogenic analysis on this set of samples using bioinformatic tools that predict the pathogenicity of variant combinations. We used two different approaches, a cohort-based approach in 240 patients and an individual approach in six severely affected patients. RESULTS Monogenic pathogenic variants were identified in 16 patients. Oligogenic cohort-based analysis identified 12 gene combinations significantly overrepresented in cases compared to controls. Individual-based analysis identified networks of variants in six patients. Manual curation of each of the variant combinations and phenotypes could not definitively confirm pathogenicity, and all combinations were finally discarded. SIGNIFICANCE Although we could not identify any definite oligogenic combination, our study shows that individual oligogenic analysis is implementable in selected patients and represents a feasible addition to monogenic analysis.

Compound Heterozygous ATM Variants Cause Adolescent‐Onset Cerebellar and Extrapyramidal Disease Without Telangiectasia in a Consanguineous Pakistani Family

Ataxia–telangiectasia (A–T) is a heterogeneous genetic disorder with a recessive mode of inheritance resulting from biallelic variants in the A–T mutated gene (ATM). Besides ataxia, the disorder involves compromised immunity and an increased risk of malignancies. We recruited a consanguineous Pakistani family with multiple individuals having adolescent‐onset ataxia. Phenotyping and clinical testing were completed for the patients. DNA samples from multiple individuals were used for bidirectional exome sequencing at 100X coverage, and data were aligned to the hg19 genome assembly. Sanger sequencing was completed to confirm the segregation of the variants. Multiple sequence alignments of orthologous proteins from diverse species were performed using ClustalO to check the amino acid conservation. Patients in the family manifested gait and limb ataxia, postural instability, and dystonia. A known heterozygous pathogenic nonsense ATM variant, c.2413C > T, p.(Arg805Ter), in trans with a new unreported missense variant, c.8708C > T, p.(Pro2903Leu), was identified, which segregated with the disease. The missense variant affected an amino acid, which was conserved in evolution. Telangiectasia of the eyes and skin was absent in the affected individuals, which led to the initial misdiagnosis of the disease as cerebellar ataxia. There were no reports of malignancies in the family, and affected individuals were alive in their third and fourth decades of life. Thus, molecular analyses resulted in the reclassification of the disease as A–T, an example of reverse phenotyping. The study expands the phenotypic heterogeneity of A–T and extends the allelic spectrum of ATM variants.