The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43.

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1-2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex-influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre-symptomatic diagnosis has the greatest clinical utility.

Genetic analysis of the FUS/TLS gene in essential tremor.

BACKGROUND AND PURPOSE: Although essential tremor (ET) has a genetic basis, specific genes have not been identified. Recently, in a large ET family (FET1) from Quebec, a non-sense mutation (p.Q290X) in the amyotrophic lateral sclerosis (ALS) gene fused in sarcoma/translated in liposarcoma (FUS/TLS) was identified by exome sequencing. No confirmatory studies have been published. METHODS: Two-hundred and fifty-nine ET cases and 262 controls were enrolled in a study at Columbia University. We performed a comprehensive analysis of the FUS/TLS gene by sequencing all exons in a subsample of 116 ET cases with early-onset (≤40 years) ET. We evaluated an association between ET and SNPs in the FUS/TLS gene by genotyping four haplotype tagging SNPs in all 259 ET cases and 262 controls. Additionally, seven variants associated with ALS, two variants of unknown pathogenicity detected in ALS cases, eight mis-sense variants predicted to be damaging, and six rare variants were genotyped in these 259 ET cases and 262 controls. RESULTS: FUS/TLS mutations previously reported in ALS, the FET1 family, or novel mutations were not found in any of the 116 early-onset ET cases. In the case-control analyses, although the power of the performed associations was limited, no significant association between tagging SNPs in FUS/TLS and ET was observed, and none of the analyzed SNPs showed evidence of association with ET. CONCLUSION: Our study suggests that pathogenic mutations in FUS/TLS are rare in a sample of early-onset ET cases in North America. We did not find evidence that the FUS/TLS gene is a risk factor for ET.

Recent advances in the genetics of distal hereditary motor neuropathy give insight to a disease mechanism involving copper homeostasis that may extend to other motor neuron disorders.

Distal hereditary motor neuropathy (dHMN) is a sub-group of Charcot-Marie-Tooth disease (CMT), the most common peripheral neuropathy, that affects only motor neurons. The recent observation of ATP7A mutations in dHMN provides insight for a common disease mechanism that may involve copper homeostasis. Functionally, diverse proteins were previously shown to underlie dHMN and a convergent link is destined to unfold for some of these. We propose connections between copper and known dHMN genes that overlap also with the causative genes of other motor neuron disorders (MNDs).