Computational protocol: A de novo Ser111Thr variant in aquaporin-4 in a patient with intellectual disability, transient signs of brain ischemia, transient cardiac hypertrophy, and progressive gait disturbance

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Protocol publication

[…] Whole-exome sequencing was performed on trios on genomic DNA isolated from blood. DNA samples were prepared using the SeqCap EZ HGSC VCRome (Roche NimbleGen) and followed by paired-end 150-nt sequencing on the Illumina NextSeq500. Alignment and variant calling was performed as described in . Median coverage of the target region was 95× with 96% of target region covered with at least 10 reads (). Data annotation and interpretation were performed using the Cartagenia Bench Lab, NGS module (Cartagenia). Filtering was set to find de novo, autosomal recessive, and X-linked causes of disease (the latter not excluding variants carried by the mother). Two de novo variants were found in the exome: AQP4(NM_001650.4) c.332G>C, p.(Ser111Thr) with 32/34 reads, and NPEPL1(NM_024663.3) c.1302+1G>T with 17/12 reads (wild-type read count listed first). The latter gene probably encodes an aminopeptidase that removes unsubstituted amino-terminal amino acids from various peptides, and the gene has high tolerance for LoF with a pLI of 0.00 (). No homozygosity or compound heterozygosity for possibly pathogenic variants was detected, including when only rare missense variants were evaluated. The AQP4 variant was verified by Sanger sequencing. Despite discrepant scores by in silico variant assessment programs (MutationTaster score 1—disease causing, SIFT score 0.04—deleterious, PolyPhen score HumDiv 0.015—benign, PolyPhen score HumVar 0.040—benign) (), this de novo variant was considered interesting because the patient's phenotype was suggestive of a problem that in theory could be caused by water imbalance in the brain and heart. […]

Pipeline specifications

Software tools MutationTaster, SIFT, PolyPhen
Application WES analysis
Organisms Homo sapiens
Diseases Brain Ischemia, Movement Disorders, Cardiomyopathies