ABSTRACTBackgroundStudies in the field of genomic secondary findings (SF) are diverse regarding participants’ characteristics; sequencing methods; versions of the ACMG SF gene list.Aim and methodsBased on whole genome sequencing (WGS) and... more
ABSTRACTBackgroundStudies in the field of genomic secondary findings (SF) are diverse regarding participants’ characteristics; sequencing methods; versions of the ACMG SF gene list.Aim and methodsBased on whole genome sequencing (WGS) and version 3.1 of ACMG SF list (ACMG SF), we studied SF in 863 individuals from Pakistan: 62% males; 80% had consanguineous parents. In addition to the ACMG SF we have generated a list of gene-disease pairs that have a clear epidemiological and medically actionable value (non-ACMG SF) in Pakistan.ResultsThe total rate of SF was 4.6%, with rates of ACMG SF – 2.7% and non-AGMG SF – 1.9%. 75.0% of ACMG SF were related to cardiovascular diseases (CVD); cancer predisposition syndromes accounted for 16.7%. Among non-ACMG SF 18.8% belong to eye diseases, followed by neuromuscular – 12.5%, metabolic – 12.5%, and urinary system diseases – 12.5%; CVD accounted for 6.3%. We found high proportion of biallelic mutations among both ACMG (4.2%) and non-ACMG (50%) SF...
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See Karakaya and Wirth (doi:10.1093/brain/awz273) for a scientific commentary on this article.Neurofascin (NFASC) isoforms are immunoglobulin cell adhesion molecules involved in node of Ranvier assembly. Efthymiou et al. identify... more
See Karakaya and Wirth (doi:10.1093/brain/awz273) for a scientific commentary on this article.Neurofascin (NFASC) isoforms are immunoglobulin cell adhesion molecules involved in node of Ranvier assembly. Efthymiou et al. identify biallelic NFASC variants in ten unrelated patients with a neurodevelopmental disorder characterized by variable degrees of central and peripheral involvement. Abnormal expression of Nfasc155 is accompanied by severe loss of myelinated fibres.
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Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early onset, therapy resistant seizures and developmental delay. Here we report on 12 individuals from 10 families... more
Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early onset, therapy resistant seizures and developmental delay. Here we report on 12 individuals from 10 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly and visual disturbance. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A>G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in brain cell types, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modelled during pluripotent stem cell differentiation in vitro. In ...