ABSTRACT
ZNF711 is one of eleven zinc-finger genes on the X chromosome that have been associated with X-linked intellectual disability. This association is confirmed by the clinical findings in 20 new cases in addition to 11 cases previously reported. No consistent growth aberrations, craniofacial dysmorphology, malformations or neurologic findings are associated with alterations in ZNF711. The intellectual disability is typically mild and coexisting autism occurs in half of the cases. Carrier females show no manifestations. A ZNF711-specific methylation signature has been identified which can assist in identifying new cases and in confirming the pathogenicity of variants in the gene.
Subject(s)
Autistic Disorder , Intellectual Disability , Autistic Disorder/genetics , DNA Methylation , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Female , Genes, X-Linked , Humans , Intellectual Disability/geneticsSubject(s)
Ectodermal Dysplasia/diagnosis , Ectodermal Dysplasia/genetics , Genes, Dominant , Limb Deformities, Congenital/diagnosis , Limb Deformities, Congenital/genetics , Phenotype , Scalp Dermatoses/congenital , Adolescent , Adult , Child , Child, Preschool , Disease Progression , Fatal Outcome , Female , Humans , Male , Scalp Dermatoses/diagnosis , Scalp Dermatoses/genetics , Young AdultABSTRACT
Both nuclear and mitochondrial DNA mutations can cause energy generation disorders. Respiratory chain complex I deficiency is the most common energy generation disorder and a frequent cause of infantile mitochondrial encephalopathies such as Leigh's disease and lethal infantile mitochondrial disease. Most such cases have been assumed to be caused by nuclear gene defects, but recently an increasing number have been shown to be caused by mutations in the mitochondrially encoded complex I subunit genes ND4, ND5, and ND6. We report the first four cases of infantile mitochondrial encephalopathies caused by mutations in the ND3 subunit gene. Three unrelated children have the same novel heteroplasmic mutation (T10158C), only the second mutation reported in ND3, and one has the previously identified T10191C mutation. Both mutations cause disproportionately greater reductions in enzyme activity than in the amount of fully assembled complex I, suggesting the ND3 subunit plays an unknown but important role in electron transport, proton pumping, or ubiquinone binding. Three cases appear to have a de novo mutation, with no mutation detected in maternal relatives. Mitochondrial DNA disease may be considerably more prevalent in the pediatric population than currently predicted and should be considered in patients with infantile mitochondrial encephalopathies and complex I deficiency.
