Table 4.

Disease-causing pathogenic variants identified by WES in group 2, consisting of patients with a possible mitochondrial disorder.

	Family	Patients	Symptoms (key features)	Biochemistry (muscle or fibroblasts)	MDC Score	Orientation	Inheritance	Mito Carta	Gene (published by our group)	Pathogenic variant
Autosomal recessive,X-linked(consanguineous, >1 patient)	Consanguineous	2	SNHL, intellectual disability, cerebellar ataxia, peripheral neuropathy, mtDNA copy number increase	Normal	4	Homozygous	AR	Yes	CLPP Theunissen et al., 2016	c.21delA, p.(Ala10Profs*117)
	Consanguineous	1	Exercise intolerance, myopathy, ataxia, diabetes mellitus	CI and CIV deficiency	4	Homozygous	AR	Yes	SLC25A32 (Hellebrekers et al., 2017)	c.-264_31delinsCTCACAAATGCTCA, deletes start codon
	Consanguineous	1	Limb girdle muscular dystrophy	n.d.	2	Homozygous	AR	No	CAPN3	c.1906C>T, p.(Gly636*)
	Consanguineous	1	Spastic diplegia, psychomotor retardation	Normal	2	Homozygous	AR	No	AP4M1	c.952C>T, p.(Arg318*)
	Consanguineous	1	Encephalopathy, psychomotor retardation, epilepsy, spastic tetraplegia	CI deficiency	3	Homozygous	AR	No	ADD3	c.1100G>A, p.(Gly367Asp)
	Consanguineous	1	Muscle weakness, SNHL, hypotonia, peripheral neuropathy	Normal	4	Homozygous	AR	No	LMOD3	c.112delG, p.(Glu38Lysfs*15)
	Non-consanguineous	2	Rhabdomyolysis	Normal	3	Homozygous	AR	No	LPIN1	c.1162C>T, p.(Arg388*)
	Consanguineous	2	Encephalopathy, liver failure, psychomotor retardation	Normal	4	Homozygous	AR	No	NBAS	c.1556T>A, p.(Val519Gln)
	Non-consanguineous	2	Congenital myopathy, spasticity	Normal	4	Compound heterozygous	AR	No	SCN4A	c.2979C>A, p.(Cys993*); c.4949C>T, p.(Pro1650Leu)
	Consanguineous	1	NBIA, microcephaly, epilepsy, psychomotor retardation, cerebellar atrophy	n.d.	3	Compound heterozygous	AR	No	RELN	c.4228G>A, p.(Gln1410Lys); c.6866C>T, p.(Thr2289Ile)
Autosmal recessive,X-linked,autosomal dominant(non -consanguineous,1patient)	Non-consanguineous	1	Psychomotor retardation, IBD deficiency, elevated C4-acylcarnitine, PEO	n.d.	4	Homozygous, dominant inherited∧	AR, AD	Yes, yes	ACAD8, DNA2	c.289G>A, p.(Gly97Arg); c.2036_2037insAA, p.(His679Glnfs*10)
	Non-consanguineous	1	Cerebellar atrophy, ataxia, dystonia	Normal	2	Compound heterozygous	AR	No	CWF19L1	c.37G>C, p.(Asp13His); c.946A>T, p.(Lys316*)
	Non-consanguineous	1	Myopathy, muscle weakness, hypotonia	n.d.	3	de novo	AD	No	ACTA1	c.16G>A, p.(Gln6Lys)
	Non-consanguineous	1	Epilepsy, hypomyelination, hypotonia, respiratory problems	Normal	4	de novo	AD	No	PURA	c.802G>T, p.(Gly268*)
	Non-consanguineous	1	Myopathy, epilepsy	Normal	3	de novo	AD	No	DYNC1H1	c.3364T>C, p.(Ser1122Pro)
	Non-consanguneous	1	Cerebellar ataxia, psychomotor retardation, extrapyramidal syndrome, axonal polyneuropathy	Normal	5	de novo	AD	No	CTNNB1	c.1511G>A, p.(Trp504*)
	Non-consanguineous	1	Psychomotor retardation, epilepsy, NBIA, retinitis pigmentosa, myopathy	Normal	5	X-linked de novo	D	No	WDR45	c.400C>T, p.(Arg134*)
	Non-consanguineous	1	Ataxia, spasticity, psychomotor retardation, cerebellar atrophy, encephalopathy	Normal	4	X-linked de novo (mosaic)	D	No	CASK	c.1061T>G, p.(Leu354Arg)

Overview of the gene defects identified by WES in 94 patients, of which 18 had a possible mitochondrial disease-cause. Patients were grouped according to the applied WES-data filtering strategy. AR, autosomal recessive; AD, autosomal dominant; D, dominant; ‘green’ marked genes, genes with a reported mitochondrial function or localization in literature; ‘red’ marked genes, no mitochondrial localization or function reported.