Lack of genotype-phenotype correlation in Brugada Syndrome and Sudden Arrhythmic Death Syndrome families with reported pathogenic SCN1B variants
Küçük Resim Yok
Tarih
2018
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Elsevier Science Inc
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
BACKGROUND There is limited evidence that Brugada Syndrome (BrS) is due to SCN1B variants (BrS5). This gene may be inappropriately included in routine genetic testing panels for BrS or Sudden Arrhythmic Death Syndrome (SADS). OBJECTIVE We sought to characterize the genotype-phenotype correlation in families who had BrS and SADS with reportedly pathogenic SCN1B variants and to review their pathogenicity. METHODS Families with BrS and SADS were assessed from 6 inherited arrhythmia centers worldwide, and a comprehensive literature review was performed. Clinical characteristics including relevant history, electrocardiographic parameters and drug provocation testing results were studied. SCN1B genetic testing results were reclassified using American College of Medical Genetics criteria. RESULTS A total of 23 SCN1B genotype-positive individuals were identified from 8 families. Four probands (17%) experienced ventricular fibrillation or sudden cardiac death at the time of presentation. All family members were free from syncope or ventricular arrhythmias. Only 2 of 23 genotype-positive individuals (9%) demonstrated a spontaneous BrS electrocardiographic pattern. Drug challenge testing for BrS in 87% (13 of 15) was negative. There was no difference in PR interval (161 +/- 7 ms vs 165 +/- 9 ms; P = .83), QRS duration (101 +/- 6 ms vs 89 +/- 5 ms; P = .35), or corrected QT interval (414 +/- 35 ms vs 405 +/- 8 ms; P = .7) between genotype-positive and genotype-negative family members. The overall frequency of previously implicated SCN1B variants in the Genome Aggregation Database browser is 0.004%, exceeding the estimated prevalence of BrS owing to SCN1B (0.0005%), including 15 of 23 individuals (65%) who had the p.Trp179X variant. CONCLUSION The lack of genotype-phenotype concordance among families, combined with the high frequency of previously reported mutations in the Genome Aggregation Database browser, suggests that SCN1B is not a monogenic cause of BrS or SADS.
Açıklama
Anahtar Kelimeler
Brugada Syndrome, Genotype-phenotype correlation, Reclassification, SADS, SCN1B, Sudden cardiac death
Kaynak
Heart Rhythm
WoS Q Değeri
Q1
Scopus Q Değeri
Q1
Cilt
15
Sayı
7
