ClinVar Genomic variation as it relates to human health

This variant, formerly titled MITOCHONDRIAL COMPLEX I DEFICIENCY, has been reclassified based on a review of the ExAC database by Hamosh (2017). In 2 first-cousin males, related by the maternal line, with a progressive neurodegenerative disorder and complex I deficiency (301020), Potluri et al. (2009) identified a 111G-C transversion in the NDUFA1 gene, resulting in a gly32-to-arg (G32R) substitution at a highly conserved residue in a hydrophilic domain close to the outer surface of the inner membrane and adjacent to the transmembrane anchor. Expression of the G32R substitution in a hamster cell line caused complex I activity to be reduced by 41% compared to wildtype, and the mutant cells showed poor growth. Patient muscle also showed variants in other mitochondrial-encoded genes, which may have contributed to the phenotype. Both patients had early normal development and then showed progressive loss of motor and cognitive functions around age 4 to 5 years. Other features included seizures, ataxia, and loss of speech. One had retinitis pigmentosa and cerebellar atrophy, and the other had sensorineural hearing loss. Muscle biopsies showed significantly decreased complex I activity (5-10% of normal). Family history revealed a maternal uncle who developed ataxia and mental retardation at age 4 years and committed suicide at age 35 years. Mayr et al. (2011) identified a heterozygous G32R substitution, resulting from a 94G-C transversion in the NDUFA1 gene, in a girl with a very mild form of complex I deficiency. She presented at age 11 months with recurrent episodes of vomiting and phases of somnolence associated with mildly increased plasma lactate. Development was normal, except for recurrent similar episodes during intercurrent illnesses. At age 5 years, she had normal psychomotor and speech development with no other abnormalities. Laboratory studies during the acute episodes suggested a defect in the mitochondrial respiratory chain. There was decreased complex I staining in muscle only, and muscle cDNA showed predominant expression of the mutant allele (72%); in addition, the patient had higher expression of the paternal AR receptor in muscle, indicating skewed X inactivation. Neither parent had the mutation in blood, suggesting either a de novo event or somatic mosaicism. Hamosh (2017) found the c.111G-C variant in 475 hemizygotes and 1 homozygote of non-Finnish Europeans in the ExAC database (December 14, 2017), giving an allele frequency of 0.0099. (less)

Failure to thrive (present) , Short stature (present) , Abnormality of movement (present) , Generalized hypotonia (present) , Abnormality of coordination (present) , Cognitive impairment (present) , Stereotypy (present) , Abnormality of the musculature of the limbs (present) , Abnormality of muscle physiology (present) , Abnormality of the large intestine (present) , Feeding difficulties (present) , Recurrent infections (present) (less)