Molecular analysis and prenatal diagnosis of seven Chinese families with genetic epilepsy

Abstract

IntroductionGenetic epilepsy is a large group of clinically and genetically heterogeneous neurological disorders characterized by recurrent seizures, which have a clear association with genetic defects. In this study, we have recruited seven families from China with neurodevelopmental abnormalities in which epilepsy was a predominant manifestation, aiming to elucidate the underlying causes and make a precise diagnosis for the cases.MethodsWhole-exome sequencing (WES) combined with Sanger sequencing was used to identify the causative variants associated with the diseases in addition to essential imaging and biomedical examination.ResultsA gross intragenic deletion detected in MFSD8 was investigated via gap-polymerase chain reaction (PCR), real-time quantitative PCR (qPCR), and mRNA sequence analysis. We identified 11 variants in seven genes (ALDH7A1, CDKL5, PCDH19, QARS1, POLG, GRIN2A, and MFSD8) responsible for genetic epilepsy in the seven families, respectively. A total of six variants (c.1408T>G in ALDH7A1, c.1994_1997del in CDKL5, c.794G>A in QARS1, c.2453C>T in GRIN2A, and c.217dup and c.863+995_998+1480del in MFSD8) have not yet been reported to be associated with diseases and were all evaluated to be pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines.MethodsBased on the molecular findings, we have associated the intragenic deletion in MFSD8 with the mutagenesis mechanism of Alu-mediated genomic rearrangements for the first time and provided genetic counseling, medical suggestions, and prenatal diagnosis for the families. In conclusion, molecular diagnosis is crucial to obtain improved medical outcomes and recurrence risk evaluation for genetic epilepsy.

Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy: QARS1 new variants associated with a severe phenotype in a patient

“…For each patient's genotype, variants lie in two different domains; the connective polypeptide 1 and the CATD domains, but these domains are structurally and functionally close related [15]. The mild phenotype noted in these patients might be explained by a more attenuated effect of compound heterozygote variants lying in closely related domains, on disrupting the proper folding of the GlnRS enzyme compared to compound heterozygote variants located in structurally and functionally different domains, like the CATD and the ABD domains, reported in other patients in the literature [1,3,6,11] as well as in our patient.…”

“…Whole exome sequencing was performed on the patient's DNA at an accredited diagnostic company (CENTOGENE GmbH) and revealed two heterozygous variants in QARS1; NM_005051. A recent study reported c.794 G A variant in a patient presenting with epilepsy and intellectual disability and classi ed it as likely pathogenic (LP: PM2 + PM3 + PP1 + PP4) in conformity with the American College of Medical Genetics and Genomics (ACMG) guidelines [3]. The second c.2234 G A variant has not been previously reported in the literature in individuals affected by MSCCA.…”

“…So far, reported QARS1 pathogenic or likely pathogenic variants are either truncating or missense, spread all over the coding sequence and are at the homozygous or compound heterozygous state within the MSCCA genotypes [1,3,6,[8][9][10][11][12][13][14]. Truncating QARS1 variants associated with MSCCA occur at one allele and are drastic for either the catalytic or the tRNA binding function of the GlnRS enzyme.…”

“…Progressive microcephaly, almost constant in MSCCA patients, is likely due to cortical volume loss and can be associated with neurodevelopmental defects like pachygyria and cortical dysplasia [3,6]. This sign can be congenital or progressive and early detected in children affected by MSCCA and lacking seizures or before developing this symptom [6,9].…”