Large copy number variations in combination with point mutations in the TYMP and SCO2 genes found in two patients with mitochondrial disorders

Abstract

Mitochondrial disorders are caused by defects in mitochondrial or nuclear DNA. Although the existence of large deletions in mitochondrial DNA (mtDNA) is well known, deletions affecting whole genes are not commonly described in patients with mitochondrial disorders. Based on the results of whole-genome analyses, copy number variations (CNVs) occur frequently in the human genome and may overlap with many genes associated with clinical phenotypes. We report the discovery of two large heterozygous CNVs on 22q13.33 in two patients with mitochondrial disorders. The first patient harboured a novel point mutation c.667G4A (p.D223N) in the SCO2 gene in combination with a paternally inherited 87-kb deletion. As hypertrophic cardiomyopathy (HCMP) was not documented in the patient, this observation prompted us to compare his clinical features with all 44 reported SCO2 patients in the literature. Surprisingly, the review shows that HCMP was present in only about 50% of the SCO2 patients with non-neonatal onset. In the second patient, who had mitochondrial neurogastrointestinal encephalopathy (MNGIE), a maternally inherited 175-kb deletion and the paternally inherited point mutation c.261G4T (p.E87D) in the TYMP gene were identified.

Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

“…The TYMP gene has been mapped to the chromosomal locus 22q13.32-qter (Hirano et al, 1998; Nishino et al, 1999, 2000). Since the identification of TYMP as the gene responsible for MNGIE, 92 different mutations have been reported by the Human Gene Mutation Database (HGMD Professional 2018.2, accessed September 2018) (Stenson et al, 2014), including 56 missense/nonsense (Nishino et al, 1999, 2000; Gamez et al, 2002; Kocaefe et al, 2003; Hirano et al, 2004b; Martín et al, 2004; Marti et al, 2005; Said et al, 2005; Slama et al, 2005; Carod-Artal et al, 2007; Schupbach et al, 2007; Monroy et al, 2008; Massa et al, 2009; Poulton et al, 2009; Bariş et al, 2010; Garone et al, 2011; Nalini and Gayathri, 2011; Scarpelli et al, 2012; Mihaylova et al, 2013; Suh et al, 2013; Benureau et al, 2014; Vondrácková et al, 2014; Peedikayil et al, 2015; Wang et al, 2015; Karyampudi et al, 2016), 13 splice site mutations (Nishino et al, 1999, 2000; Kocaefe et al, 2003; Szigeti et al, 2004b; Slama et al, 2005; Laforce et al, 2009; Taanman et al, 2009; Garone et al, 2011; Libernini et al, 2012; Halter et al, 2015), 13 small deletions (Nishino et al, 1999, 2000; Blazquez et al, 2005; Slama et al, 2005; Poulton et al, 2009; Filosto et al, 2011; Garone et al, 2011; Torres-Torronteras et al, 2011; Halter et al, 2015; Karyampudi et al, 2016), 6 small insertions (Nishino et al, 1999; Gamez et al, 2002; Hirano et al, 2004b; Kintarak et al, 2007; Poulton et al, 2009; Cardaioli et al, 2010), 2 small indels (Garone et al, 2011; Libernini et al, 2012) 1 gross insertion (Wang et al, 2017) and 1 gross deletion (Vondrácková et al, 2014). These mutations have been mapped to either exonic or intronic regions, with some identified as benign and some as pathogenic variants.…”

Mitochondrial Dysfunction may explain symptom variation in Phelan-McDermid Syndrome

“…This “neighboring effect” could explain the lack of specific genotype-phenotype and why there was no specific association between abnormalities in ETC Complex I activity and a specific deletions of the NDUFA6 gene. Alternatively, intact genes within regions of large chromosomal deletions have been shown to have point mutation, resulting in expression of recessive mitochondrial disorders 10 . This suggests that the same pathological processes that caused the copy number variation may also cause smaller changes in nearby genes that would not be detected by microarray.…”

“…Recently, Frye 4 noted that 6 mitochondrial genes are proximal to the SHANK3 gene within the 22q13 region, suggesting that copy number variations in this chromosomal region may have the potential to cause abnormal mitochondrial function. These genes include those essential for complex I (NDUFA6) and IV (SCO2) function of the electron transport chain (ETC) as well as mitochondrial DNA (TYMP), RNA (TRMU) and fatty acid (CPT1B) metabolism and tricaboxylic acid cycle function (ACO2) 5 6 7 8 9 10 11 12 13 14 15 16 17 18 . Table 1 outlines these genes as well as the mitochondrial diseases with which they have been associated.…”

Severe Hypokalemic Paralysis as a Manifestation of a Mitochondrial Disorder

“…MtD was suspected because of the clinical presentation with occasional double vision and ptosis since 10 years earlier, hypertelorism, brachydactylia, renal insufficiency, bilateral progressive renal cysts, the suprarenal adenomas, hypertriglyceridemia, arterial hypertension, hypertrophic cardiomyopathy with a restrictive filling pattern, and psoriasis. Left ventricular hypertrophy was attributed to the suspected genetic defect because blood pressure was well controlled, hypertrophic cardiomyopathy has been reported as a mani- festation of MtD (Palecek et al 2012;Vondráčková et al 2013), and because left ventricular hypertrophy was extensive. Hypertelorism and brachydactylia were also suggestive of MtD since they have been reported as MtD manifestations (Pronicki et al 2002;Finsterer 2011).…”