Family-11COQ5c.933delCp.(Tyr311*)0.00001760Disease causingP (PVS1, PM2, PP3)–This study(GC21390)c.682-7 T > Gp.(Gln230*); p.(Leu193Phefs*27)0.001434See suppl. Table 1VUS (PM2, PM3, BP4)–This study

Family-12COQ5c.367 C > Tp.(Arg123Trp)0.00003266Disease causingVUS (PM2, PP3)–This studyc.682-7 T > Gp.(Gln230*); p.(Leu193Phefs*27)0.001434See suppl. Table 1VUS (PM2, PM3, BP4)–This study

These data were combined through CATCH,37 and after analysis of the results, three variants remained for further evaluation (Table S1) in genes PIGG (c.928C>T [p.Gln310∗] [GenBank: {"type":"entrez-nucleotide","attrs":{"text":"NM_001127178.2","term_id":"573459749","term_text":"NM_001127178.2"}}NM_001127178.2]), COQ5 (MIM: 616359; c.319G>A [p.Gly107Arg] [GenBank: {"type":"entrez-nucleotide","attrs":{"text":"NM_032314.3","term_id":"116063535","term_text":"NM_032314.3"}}NM_032314.3]), and RGS12 (MIM: 602512; c.188A>T [p.Gln63Leu] [GenBank: {"type":"entrez-nucleotide","attrs":{"text":"NM_002926.3","term_id":"108773791","term_text":"NM_002926.3"}}NM_002926.3]). All variants were confirmed by Sanger sequencing, and family segregation confirmed that the affected individuals, as well as the unaffected siblings, are heterozygous for the variants (Figure 3A). Variants in PIGG and COQ5 are not present in publically available databases, whereas the variant in RGS12 has a cumulative frequency of 4.95e−5 in the Exome Aggregation Consortium (ExAC) Browser.43 The variant in PIGG is nonsense, whereas the other two are missense.Open in a separate windowFigure 3Identified Variants(A) Sequencing chromatograms of the identified variant in family EG. The parents and unaffected siblings are heterozygous, whereas the affected individuals are homozygous for the c.928C>T mutation (noted by the black arrow).(B) Sequencing chromatograms of the identified variant in family JP. The father has the heterozygous c.2005C>T variant, but the mother does not (noted by the black arrow).(C) XHMM analysis using WES data of individual JP01. A microdeletion involving PIGG (chr4: 60,226–2,452,836) is indicated.(D) qPCR analysis of exons 7 and 12 of the PIGG genome from individual JP01 and her parents shows a heterozygous PIGG deletion in the affected individual, but not in her mother, suggesting that the deletion occurred de novo on the maternal chromosome.(E) Sequencing chromatograms of the identified variant in family PK are noted by the blue transparent boxes. The parents are heterozygous, and the affected individuals are homozygous for the c.2261+1G>C mutation.PIGG was considered the most prominent candidate because the variant identified causes a clear loss of function. A recent inquiry of the ExAC Browser verified that no homozygous loss-of-function variants have been reported and that the most common loss-of-function variant, c.1515G>A (p.Trp505∗) (GenBank: {"type":"entrez-nucleotide","attrs":{"text":"NM_001127178.2","term_id":"573459749","term_text":"NM_001127178.2"}}NM_001127178.2), has a minor allele frequency (MAF) of 0.0012 in the European population. This translates to a frequency of less than 1 in 600,000 individuals, compatible with a rare autosomal-recessive disorder.

A total of 801 stroke patients were enrolled in the study (Figure 1). We excluded 91 patients who did not have muscle symptoms with CK elevation or had tolerable myalgia without CK elevation. Seven patients were excluded because their baseline CK levels were not less than 480 U/L. Eleven patients were excluded because their CK levels were elevated by other medical issues including myocardial infarction and surgical procedures. We also excluded four patients as their DNA samples were insufficient for analysis. As a result, 688 patients were included in the analysis. Of the included patients, 56 experienced statin-associated muscle symptoms. Twelve patients underwent myopathy (SRM 3) after statin treatment, and two patients experienced severe myopathy (SRM 4). Forty-two patients had intolerable myalgia (SRM 2). The remaining 632 patients who never experienced SRM were classified as the control group.

M144NS COQ5 G118S1.815.10P, E; methyltransferase with pivotal role in coenzyme Q biosynthesis. Interacts with NAB2 which controls length of poly(A) tail (see http://thebiogrid.org/35094/summary/saccharomyces-cerevisiae/coq5.html). The human orthologue of NAB2 is implicated in ARID32.

Patient historyWe present a Polish female patient current age 10 years, born at term by natural delivery at the 39th week of the mother’s first pregnancy. Parents were healthy, non-consanguineous, Caucasian in origin. At the time of birth, the mother was 29 years old; the father was 33 years old.Family history was negative for individuals with neurodevelopmental disorders. Patient birth body parameters were the following: body weight: 3380 g (50 pc); body length: 54 cm (<95 pc); occipital frontal circumference: 31 cm (<3 pc). Apgar scores were 10 points at 1 and 5 min of life.Presented girl displayed normal, uneventful postnatal adaptation and development from birth to 5 months of life.At 22 weeks, directly after third dose-vaccination with DTaP (Infanrix-Hexa), motor and cognitive regression, deterioration of eye contact, and the lack of a smile were noticed. Consequently, further vaccinations were suspended. At the age of 18 months, further developmental regression became apparent. She was intensively rehabilitated, but no progress was observed. In clinical evaluation, she could not stand up or walk independently and she could pronounce a few simple syllables and try to combine them into words. Detailed clinical observations from 1.5 to 10 years of age are described in supplementary data.At the age of 10 years, she had not acquired the ability to walk; cognitive development remains at a low level. Summary of neurological examinations showed global developmental delay, tetraparesis with hypotonia and symmetrical tendon reflexes, limited eye contact, postural defects including a “rounded” back, protruding shoulder blades, and funnel-shaped chest (Fig. ​(Fig.1aIII–IV).1aIII–IV). Phenotypic evaluation of the face revealed slight ptosis, a tendency to open the mouth and tilt the head back, without other specific features of dysmorphism (Fig. ​(Fig.11aI).Open in a separate windowFig. 1a Photographic documentation of the patient at age 10 years old. b COQ5 cDNA gel electrophoresis. c Graphical representation of the splicing products of the COQ5 gene in a patient, her parents, and healthy control. For more details, please see supplementary dataExploratory assaysMagnetic resonance imaging (MRI) of the brain at the age of 8 years revealed clear cortico-subcortical atrophy of the cerebellum–enlargement of the 4th ventricle and widening of cerebellar sulci (Supp.Fig.1a-d, arrows) as compared to the normal appearance in a healthy individual (Supp.Fig.1e-h, arrows). The cerebellar sulci were wider in our patient at age 8 years than at 18 months, as well as in comparison to an age-matched healthy control. This indicates progressive atrophy of cerebellar tissue. Atrophy involved both vermis and cerebellar hemispheres. The supratentorial structures are normal. Echocardiogram, abdominal ultrasonography, and ophthalmologic investigation were also uneventful.