Mutations inCOQ4, an essential component of coenzyme Q biosynthesis, cause lethal neonatal mitochondrial encephalomyopathy

Abstract

Mutations in COQ4 cause an autosomal recessive lethal neonatal mitochondrial encephalomyopathy associated with a founder mutation in the Ashkenazi Jewish population. The early mortality in our cohort suggests that COQ4 is an essential component of the multisubunit complex required for CoQ(10) biosynthesis.

Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy

“…Three genes in our epilepsy cohort (COQ4, DNM1, and PURA), accounting for 14% (3/21) of all novel genetic etiologies identified in patients with epilepsy, were subsequently confirmed in independent publications. 16,[33][34][35][36] Although it is difficult to assess to what extent this frequency is higher than would be expected by chance, we feel reassured by the fact that approximately 15% of all genes that were reported as potential novel disease genes received subsequent independent confirmation without knowledge of our prior report. This number may provide a baseline for future studies examining the role of diagnostic novel gene reporting.…”

Clinical application of whole-exome sequencing across clinical indications

“…Utilizing the power of our large data set, we were able to identify novel candidate genes in which multiple patients with similar phenotypes had rare variants predicted to result in loss of function, many of which were de novo. Access to this large number of cases has proven extremely valu- [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] As a result of our experience, we believe that candidate genes should be reported from WES analysis and shared in databases, such as GeneMatcher, so that clinicians, researchers, and clinical laboratories can be connected to facilitate more rapid dissemination of information and validation of novel disease genes. Our series is larger than previously reported clinical diagnostic series and has the power to begin to address the yield of WES for a large number of clinical indications.…”

Novel recessive mutations in COQ4 cause severe infantile cardiomyopathy and encephalopathy associated with CoQ 10 deficiency

“…To date, primary CoQ 10 deficiency due to mutations in COQ4 (CoQ 10 D7, MIM616276) has been described in twelve patients from nine unrelated families. All affected patients but one harbored either homozygous or compound heterozygous mutations in the COQ4 gene [18], [19]. A single case of CoQ 10 deficiency was reported to be associated with haploinsufficiency of COQ4 [24].…”

“…However, in yeast, and possibly in mammals, at least 12 mitochondrial enzymes are known to participate in CoQ 10 biosynthesis [15]. Mutations in PDSS1 (MIM607429) [16], PDSS2 (MIM610564) [10], COQ2 (MIM609825) [16], [17], COQ4 (MIM 616227) [18], [19], COQ6 (MIM614647) [20], COQ7 (MIM616733) [21], COQ8A / ADCK3 (MIM 612016) [22], COQ8B/ADCK4 (MIM615573) [12], and CoQ9 (MIM614654) [23] genes have been described in patients with early-onset multisystemic mitochondrial encephalopathy, cardiomyopathy, and renal failure associated with severe CoQ 10 deficiency. To date, primary CoQ 10 deficiency due to mutations in COQ4 (CoQ 10 D7, MIM616276) has been described in twelve patients from nine unrelated families.…”