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ObjectiveTo determine the yield of genetic diagnoses using chromosomal microarray (CMA) and trio whole exome sequencing (WES), separately and combined, among patients with cryptogenic cerebral palsy (CP).MethodsTrio WES of patients with prior CMA analysis for cryptogenic CP, defined as disabling, non-progressive motor symptoms beginning before the age of 3 years without known cause.ResultsGiven both CMA analysis and trio WES, clinically significant genetic findings were identified for 58% of patients (26 of 45). Diagnoses were eight large CNVs detected by CMA and 18 point mutations detected by trio WES. None had more than one severe mutation. Approximately half of events (14 of 26) were de novo. Yield was significantly higher in patients with CP with comorbidities (69%, 22 of 32) than in those with pure motor CP (31%, 4 of 13; p=0.02). Among patients with genetic diagnoses, CNVs were more frequent than point mutations among patients with congenital anomalies (OR 7.8, 95% CI 1.2 to 52.4) or major dysmorphic features (OR 10.5, 95% CI 1.4 to 73.7). Clinically significant mutations were identified in 18 different genes: 14 with known involvement in CP-related disorders and 4 responsible for other neurodevelopmental conditions. Three possible new candidate genes for CP were ARGEF10, RTF1 and TAOK3.ConclusionsCryptogenic CP is genetically highly heterogeneous. Genomic analysis has a high yield and is warranted in all these patients. Trio WES has higher yield than CMA, except in patients with congenital anomalies or major dysmorphic features, but these methods are complementary. Patients with negative results with one approach should also be tested by the other.

BackgroundCopy number variants (CNVs) associated with late-onset medical conditions are rare but important secondary findings in chromosomal microarray analysis (CMA) performed during pregnancy. Here, we critically review the cases at two tertiary centres to assess the criteria which guide the disclosure of such findings and develop a disclosure decision tool (DDT) aimed at facilitating disclosure decision. Parental decisions on receiving CNVs associated with risks for late-onset conditions were also recorded.MethodsPrenatal CMAs in Hadassah and Shaare Zedek Medical Centers from November 2013 to October 2021 were reviewed for CNVs associated with late-onset conditions. The DDT proposed uses a five-parameter scoring system, which considers the severity, median age of onset, penetrance, understanding of genotype-phenotype correlation and actionability of the finding.ResultsOut of 16 238 prenatal CMAs, 16 (0.1%) harboured CNVs associated with late-onset conditions, 15 of which were disclosed. Outcome information was available on 13 of the 16 pregnancies, all of which continued to delivery.ConclusionsOur suggested DDT will help clinicians to quantitatively weigh the variables associated with CNVs of this type and arrive at a well thought out clinical decision regarding disclosure. Although the prevalence of late-onset conditions as a major finding in the prenatal setup is low, it is expected to rise with the increasing use of non-invasive CMA testing and whole exome and genome sequencing.

Background Agenesis of corpus callosum has been associated with several defects of the mitochondrial respiratory chain and the citric acid cycle. We now report the results of the biochemical and molecular studies of a patient with severe neurodevelopmental disease manifesting by agenesis of corpus callosum and optic nerve hypoplasia. Methods and results A mitochondrial disease was suspected in this patient based on the prominent excretion of 2-hydroxyglutaric acid and Krebs cycle intermediates in urine and the finding of increased reactive oxygen species content and decreased mitochondrial membrane potential in her fibroblasts. Whole exome sequencing disclosed compound heterozygosity for two pathogenic variants in the SLC25A1 gene, encoding the mitochondrial citrate transporter. These variants, G130D and R282H, segregated in the family and were extremely rare in controls. The mutated residues were highly conserved throughout evolution and in silico modeling investigations indicated that the mutations would have a deleterious effect on protein function, affecting either substrate binding to the transporter or its translocation mechanism. These predictions were validated by the observation that a yeast strain harbouring the mutations at equivalent positions in the orthologous protein exhibited a growth defect under stress conditions and by the loss of activity of citrate transport by the mutated proteins reconstituted into liposomes. Conclusions We report for the first time a patient with a mitochondrial citrate carrier deficiency. Our data support a role for citric acid cycle defects in agenesis of corpus callosum as already reported in patients with aconitase or fumarate hydratase deficiency.