RESUMEN
OBJECTIVE: Cardiomyopathy (CMP) in children is a clinically and genetically heterogeneous group of disorders. Disease-associated mutations have been identified in more than 50 genes. Recently, mutations in the mitochondrial tRNA processing gene, ELAC2, were reported to be associated with the recessively inherited form of hypertrophic CMP (HCM). This study is aimed at describing the cardiac phenotype and outcome of ELAC2 mutation. METHODS: We performed whole exome sequencing followed by targeted mutation screening to identify the genetic etiology of severe infantile-onset CMP in 64 consanguineous Saudi families. RESULTS: A previously reported mutation (p.Phe154Leu) in ELAC2 gene was detected in 16 families. The index cases presented between 2 and 7 months of age with HCM in 13 infants and dilated CMP (DCM) in 3. Pericardial effusion was observed in 7 infants (44%). All infants died with a median age of death of 4 months. Almost 1/3 of them died during the initial presentation. CONCLUSION: Our study suggests screening the ELAC2 gene in severe infantile-onset HCM or DCM of unknown etiology, especially in the presence of pericardial effusion. Our work demonstrates a universally poor outcome of the (p.Phe154Leu) variant in ELAC2 gene; a correlation that helps in counseling parents and in planning appropriate medical intervention.
Asunto(s)
Cardiomiopatía Dilatada/genética , Cardiomiopatía Hipertrófica/genética , Proteínas de Neoplasias/genética , Salud de la Familia , Femenino , Homocigoto , Humanos , Lactante , Masculino , Mutación Missense , Fenotipo , Arabia SauditaRESUMEN
Our study describes a novel phenotype in a series of nine Saudi patients with lactic acidosis, from four consanguineous families three of which are related. Detailed genetic studies including linkage, homozygosity mapping and targeted sequencing identified a causative mutation in the BCS1L gene. All affected members of the families have an identical mutation in this gene, mutations of which are recognized causes of Björnstad syndrome, GRACILE syndrome and a syndrome of neonatal tubulopathy, encephalopathy, and liver failure (MIM 606104) leading to isolated mitochondrial respiratory chain complex III deficiency. Here we report the appearance of a novel behavioral (five patients) and psychiatric (two patients) phenotype associated with a p.Gly129Arg BCS1L mutation, differing from the phenotype in a previously reported singleton patient with this mutation. The psychiatric symptoms emanated after childhood, initially as hypomania later evolving into intermittent psychosis. Neuroradiological findings included subtle white matter abnormalities, whilst muscle histopathology and respiratory chain studies confirmed respiratory chain dysfunction. The variable neuro-psychiatric manifestations and cortical visual dysfunction are most unusual and not reported associated with other BCS1L mutations. This report emphasizes the clinical heterogeneity associated with the mutation in BCS1L gene, even within the same family and we recommend that defects in this gene should be considered in the differential diagnosis of lactic acidosis with variable involvement of different organs.
Asunto(s)
Acidosis Láctica/genética , Complejo III de Transporte de Electrones/genética , Mutación , ATPasas Asociadas con Actividades Celulares Diversas , Acidosis Láctica/metabolismo , Adolescente , Adulto , Niño , Colestasis/genética , Colestasis/metabolismo , Transporte de Electrón/genética , Complejo III de Transporte de Electrones/metabolismo , Femenino , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/metabolismo , Predisposición Genética a la Enfermedad , Enfermedades del Cabello/genética , Enfermedades del Cabello/metabolismo , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/metabolismo , Hemosiderosis/genética , Hemosiderosis/metabolismo , Homocigoto , Humanos , Masculino , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Enfermedades Mitocondriales/congénito , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Fenotipo , Aminoacidurias Renales/genética , Aminoacidurias Renales/metabolismoRESUMEN
BACKGROUND: Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale. METHODS: To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either (1) targeted genetic test with targeted mutation test, single-gene test, or multigene panel for Noonan syndrome, or (2) untargeted genetic test with whole-exome sequencing or whole-genome sequencing. Several bioinformatics tools were used to filter the variants. RESULTS: Two-hundred five unrelated probands with various forms of cardiomyopathy were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates (ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1). CONCLUSIONS: Our work demonstrates the impact of consanguinity on the genetics of childhood-onset cardiomyopathy, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting whole-exome sequencing/whole-genome sequencing as a first-line test should be considered.