RESUMEN
Mitochondrial DNA (mtDNA) variant pathogenicity interpretation has special considerations given unique features of the mtDNA genome, including maternal inheritance, variant heteroplasmy, threshold effect, absence of splicing, and contextual effects of haplogroups. Currently, there are insufficient standardized criteria for mtDNA variant assessment, which leads to inconsistencies in clinical variant pathogenicity reporting. An international working group of mtDNA experts was assembled within the Mitochondrial Disease Sequence Data Resource Consortium and obtained Expert Panel status from ClinGen. This group reviewed the 2015 American College of Medical Genetics and Association of Molecular Pathology standards and guidelines that are widely used for clinical interpretation of DNA sequence variants and provided further specifications for additional and specific guidance related to mtDNA variant classification. These Expert Panel consensus specifications allow for consistent consideration of the unique aspects of the mtDNA genome that directly influence variant assessment, including addressing mtDNA genome composition and structure, haplogroups and phylogeny, maternal inheritance, heteroplasmy, and functional analyses unique to mtDNA, as well as specifications for utilization of mtDNA genomic databases and computational algorithms.
Asunto(s)
ADN Mitocondrial/genética , Variación Genética , Guías como Asunto , Sociedades Científicas , Bases de Datos Genéticas , Árboles de Decisión , Haplotipos/genética , Humanos , Fenotipo , Estándares de ReferenciaRESUMEN
Functional disorders are common conditions with a substantial impact on a patients' wellbeing, and can be diagnostically elusive. There are bidirectional associations between functional disorders and mitochondrial dysfunction. In this study, provided clinical information and the exon sequence of the TRAP1 mitochondrial chaperone were retrospectively reviewed with a focus on the functional categories of chronic pain, fatigue and gastrointestinal dysmotility. Very-highly conserved TRAP1 variants were identified in 73 of 930 unrelated patients. Functional symptomatology is strongly associated with specific variants in the ATPase binding pocket. In particular, the combined presence of all three functional categories is strongly associated with p.Ile253Val (OR 7.5, P = 0.0001) and with two other interacting variants (OR 18, P = 0.0005). Considering a 1-2% combined variant prevalence and high odds ratios, these variants may be an important factor in the etiology of functional symptomatology.
Asunto(s)
Fatiga/genética , Proteínas HSP90 de Choque Térmico/genética , Náusea/genética , Dolor/genética , Sustitución de Aminoácidos , Frecuencia de los Genes , Estudios de Asociación Genética , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Estudios RetrospectivosRESUMEN
UNLABELLED: An X-linked neurodevelopmental disorder previously had been reported in only one family, associated with a p.D59G mutation in the RAB40AL gene that encodes a mitochondrial Ras protein. The three related males described had varying degrees of cognitive impairment, sensorineural hearing loss, short stature, dysmorphic facies, and other morphological defects. CONCLUSION: We herein present an unrelated 20-year-old male with similar manifestations also with p.D59G in the RAB40AL gene, which supports the existence of this condition previously coined as Martin-Probst syndrome (OMIM: 300519).
Asunto(s)
Anomalías Múltiples/genética , Anomalías Craneofaciales/genética , Discapacidades del Desarrollo/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Pérdida Auditiva Sensorineural/genética , Discapacidad Intelectual/genética , Proteínas Mitocondriales/genética , Mutación , Anomalías Urogenitales/genética , Proteínas ras/genética , Anomalías Múltiples/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Pérdida Auditiva Sensorineural/diagnóstico , Humanos , Discapacidad Intelectual/diagnóstico , Masculino , Adulto JovenRESUMEN
Although mothers of chronically ill children are generally prone to depression and anxiety, clinical observation suggests that these symptoms are relatively increased in mothers of children with maternally inherited mitochondrial disorders (MIMD). In this study, the Beck Depression Inventory II (BDI), the Beck Anxiety Inventory (BAI), and a non-standardized mental health questionnaire were administered to 15 mothers of children with MIMD and 17 mothers of children with autosomal recessive metabolic disorders (ARMD) followed in one clinic. One half of the children in both groups suffer from mental retardation and/or > or = 2 hospitalizations/year related to their genetic disorder, and were labeled as severely affected. BDI and BAI scores were similar between mothers of severely affected MIMD and ARMD children, but BDI and BAI scores were threefold higher in mothers of mildly affected MIMD versus ARMD children (P = 0.001 and P = 0.003, respectively). Any mental health condition was self-reported in 10/15 MIMD and 2/17 ARMD mothers (P = 0.002), while at least one mental health condition per family was reported to be present in a matrilineal first-degree relative of the mother in 8/15 MIMD versus 1/17 ARMD families (P = 0.004). Our data confirm that mental health conditions, particularly depression, are diagnosed at an increased frequency among matrilineal relatives likely sharing the same mitochondrial DNA (mtDNA) as the affected proband. While previous studies have demonstrated that mtDNA sequences can affect brain function, our data suggests that in addition mtDNA sequences can predispose individuals towards the development of some "mental health" disorders. Thus, "genome-wide" studies to screen for genes associated with depression and anxiety should not neglect the small, yet important, mitochondrial genome.