Homozygous Fukutin Missense Mutation in Two Mexican Siblings with Dilated Cardiomyopathy

ABSTRACT Background: Fukuyama congenital muscular dystrophy (FCMD) is the most common form of a group of autosomal recessive disorders characterized by altered α-dystroglycan glycosylation and caused by FKTN gene mutations. However, mutations of this gene may cause a broad range of phenotypes, including Walker-Warburg syndrome, muscle-brain-eye disease, FCMD, limb-girdle muscular dystrophy without mental retardation, and cardiomyopathy with no or minimal skeletal muscle weakness. Objective: Our purpose was to describe two siblings who died at a young age with dilated cardiomyopathy (DCM), no muscle weakness, or atrophy, and were homozygous for a FKTN missense mutation. Methods: Site-directed next-generation sequencing (NGS) was performed. Pathogenicity of variants of interest was established according to the American College of Medical Genetics (ACMG) criteria, and all available first-degree relatives were screened for mutations by Sanger sequencing. Results: NGS revealed a homozygous FKTN variant in the index case (p.Gly424Ser, rs752358445), classified as likely pathogenic by ACMG criteria. Both parents and an unaffected brother were heterozygous carriers. Since the siblings had no apparent skeletal muscle weakness or central nervous system involvement, FKTN mutations were not initially suspected. Conclusions: This is the first report demonstrating that heterozygous individuals for the FKTN p.Gly424Ser mutation were healthy, while two homozygous brothers suffered severe DCM, strongly suggesting that this FKTN mutation is a rare cause of autosomal recessive DCM.

Genes frequently associated with sudden death in primary hypertrophic cardiomyopathy / Genes frecuentemente asociados con muerte súbita en miocardiopatía hipertrófica primaria

Abstract Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy without apparent cardiac justification. Sudden cardiac death may be the first manifestation of the disease. It occurs mainly in adulthood and can be seen in childhood and adolescence where genetic origin predominates. Primary HCM (“familial”) is inherited in an autosomal dominant pattern in the 25 subtypes informed in Online Mendelian Inheritance in Man. The proteins encoded by the mutated genes are part of the sarcomere in the cardiac cells, being the thick filament the most frequently affected, with the worst prognosis. In the present article, we describe the Mendelian inheritance of the disease and the two most associated genes with sudden death: MYBPC3 and MYH7.

Resumen La miocardiopatía hipertrófica (MCH) es el aumento de grosor de la pared ventricular izquierda no relacionada con otras alteraciones cardíacas. Es una enfermedad que puede presentar como primera manifestación clínica la muerte súbita y de ahí su relevancia clínica. Aunque se presenta sobre todo en la edad adulta, puede aparecer durante la infancia y adolescencia, en las que predominan los casos de origen hereditario. La MCH primaria, de causa genética, muestra en particular un patrón de herencia autosómico dominante en los 25 subtipos reconocidos en OMIM (Online Mendelian Inheritance in Man). Las proteínas codificadas por los genes mutantes forman parte del sarcómero en células musculares cardíacas, y las variantes patogénicas de filamentos gruesos son las de mayor frecuencia y peor pronóstico. En este artículo se describen la herencia mendeliana de la enfermedad y la relación con muerte súbita de los genes más frecuentemente encontrados en ella: MYBPC3 y MYH7.

Genes frequently associated with sudden death in primary hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is characterized by left ventricular hypertrophy without apparent cardiac justification. Sudden cardiac death may be the first manifestation of the disease. It occurs mainly in adulthood and can be seen in childhood and adolescence where genetic origin predominates. Primary HCM ("familial") is inherited in an autosomal dominant pattern in the 25 subtypes informed in Online Mendelian Inheritance in Man. The proteins encoded by the mutated genes are part of the sarcomere in the cardiac cells, being the thick filament the most frequently affected, with the worst prognosis. In the present article, we describe the Mendelian inheritance of the disease and the two most associated genes with sudden death: MYBPC3 and MYH7.

La miocardiopatía hipertrófica (MCH) es el aumento de grosor de la pared ventricular izquierda no relacionada con otras alteraciones cardíacas. Es una enfermedad que puede presentar como primera manifestación clínica la muerte súbita y de ahí su relevancia clínica. Aunque se presenta sobre todo en la edad adulta, puede aparecer durante la infancia y adolescencia, en las que predominan los casos de origen hereditario. La MCH primaria, de causa genética, muestra en particular un patrón de herencia autosómico dominante en los 25 subtipos reconocidos en OMIM (Online Mendelian Inheritance in Man). Las proteínas codificadas por los genes mutantes forman parte del sarcómero en células musculares cardíacas, y las variantes patogénicas de filamentos gruesos son las de mayor frecuencia y peor pronóstico. En este artículo se describen la herencia mendeliana de la enfermedad y la relación con muerte súbita de los genes más frecuentemente encontrados en ella: MYBPC3 y MYH7.

Methylenetetrahydrofolate reductase C677T and glutathione S-transferase P1 A313G are associated with a reduced risk of preeclampsia in Maya-Mestizo women.

Preeclampsia, a common complication of pregnancy, is characterized by elevated blood pressure and proteinuria developing after 20 weeks' gestational age. Susceptibility to this syndrome is believed to have a genetic component. The aim of this study was to investigate whether or not the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and glutathione S-transferase P1 (GSTP1) A313G polymorphisms are associated with preeclampsia in Maya-Mestizo women. A case-control study was performed, in which 125 preeclamptic patients and 274 healthy controls were genotyped for the MTHFR C677T and GSTP1 A313G polymorphisms by real-time PCR allelic discrimination. Allele and genotype frequencies were compared using the chi2 tests. The MTHFR 677T allele and the 677TT genotype were significantly more frequent in the controls, suggesting an association with a decreased risk of preeclampsia (p = 0.017 and p = 0.007, respectively). Similarly, GSTP1 313GG/GC genotypes and the G allele were more frequent in controls, showing a significant association with reduced risk of preeclampsia (p = 0.008 and p = 0.013, respectively). Our results suggest, for the first time, that the MTHFR 677T and GSTP1 313G polymorphisms confer a significantly decreased risk of developing preeclampsia in the Mexican Maya-Mestizo population.