MITOCHONDRIAL DISEASES (Posters): P.193Unexpected genetic diagnosis of mitochondrial disease in three consanguineous Turkish families

Abstract

Mitochondrial diseases are a clinically heterogeneous group of disorders caused by dysfunction of the mitochondrial respiratory chain. Some mitochondrial disorders affect a single organ, while many involve multiple systems such as skeletal muscle, brain, heart and liver, leading to diagnostic difficulties. Here we present three patients who were originally suspected to have a primary disease of skeletal muscle, leukodystrophy and brain malformation. Patients were recruited from three paediatric neurology clinics in Turkey: Izmir, Malatya and Diyarbakir. Whole exome sequencing (WES) was performed using Illumina exome capture (38 Mb target). Data analysis was carried out on the RD-Connect Genome-Phenome Analysis Platform (https://platform.rd-connect.eu/). Standard filtering criteria with MAF<1% and high/moderate VEP were used, as well as a list consisting of >5,000 medically interpretable genes. We identified a homozygous frameshift variant (p.Glu41GlyfsTer10) in NDUFA12 and a homozygous missense variant (p.Gln85His) in NDUFS3, both associated with Leigh syndrome due to mitochondrial complex I deficiency (OMIM# 256000). We also identifid a homozygous nonsense variant (p.His158ProfsTer8) in TACO1 associated with mitochondrial complex IV deficiency (OMIM# 220110), the second patient to be described worldwide so far. All the variants were highly pathogenic and were absent in the control population, suggesting they were disease-causing. Critical clinical review and metabolic analysis confirmed the mitochondrial deficiency. Next generation sequencing has the advantage of allowing an unbiased genetic diagnosis. We described three cases that had been initially diagnosed as myopathy, brain malformation and leukodystrophy, and WES resulted in the diagnoses of mitochondrial disorders. Importantly, this will allow for appropriate clinical management of these patients.