[email protected] (受疫情影响,东南亚目前只开放曼谷诊所)
全周 (9AM - 5PM)


Extra info thumb
  • 总部: 泰国曼谷市巴吞汪区仑披尼分区 普勒吉路齐隆巷5号.
  • [email protected]


Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance, affecting more than 2 million Americans, with an overall prevalence of 0.89%. T...

Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance, affecting more than 2 million Americans, with an overall prevalence of 0.89%. The prevalence increases rapidly with age, to 2.3% between the ages of 40 and 60 years, and to 5.9% over the age of 65. The most dreaded complication is thromboembolic stroke (Brugada et al., 1997).

For a discussion of genetic heterogeneity of atrial fibrillation, see 608583.

▼ Clinical Features
Chen et al. (2003) studied a family from Shandong Province, China, in which 16 individuals over 4 generations exhibited atrial fibrillation. The proband was identified in 1970 at the age of 22 years. Atrial fibrillation persisted in affected individuals once it appeared. Prolonged QTc interval was observed in 9 of the 16 affected individuals, ranging from 450 to 530 ms. Chen et al. (2003) stated that they had previously observed prolongation of QTc in sporadic AF patients, and suggested that the prolongation might be attributable in part to heart muscle disease secondary to AF; however, in the Chinese family, the value of the QT interval did not correlate with duration of persistent AF.

Das et al. (2009) described a family in which 7 members over 3 generations had lone AF documented on electrocardiogram (ECG). The matriarch of the family developed AF as a young adult and died of embolic stroke at age 79 years. Six of her descendants developed AF between 16 and 59 years of age, 3 with persistent AF and 3 with paroxysmal AF.

Abraham et al. (2010) studied a Caucasian kindred in which a mother and 3 children had relatively early onset of atrial fibrillation with normal QT interval. All affected individuals presented with symptomatic paroxysmal AF between 38 and 48 years of age. Two additional family members, aged 44 years and 36 years, reported episodic palpitations lasting up to 20 minutes and occurring every couple of months, but AF had not yet been documented.

Bartos et al. (2013) studied 4 families with early-onset AF (less than 40 years of age) in which a missense mutation in the KCNQ1 gene (R231H; 607542.0043) was identified in affected individuals (see MOLECULAR GENETICS). In the first family, the 20-year-old proband presented with ventricular fibrillation while sleeping and was successfully resuscitated but was then found to have AF. His mutation-positive mother, sister, and brother all had AF. In the second family, the proband was bradycardic at birth but had normal ECGs thereafter; his mother and maternal grandmother, both diagnosed with AF at 16 years of age, carried the R231H mutation, as did his asymptomatic brother. In the third family, the proband was diagnosed with AF at 14 years of age; her sister, who had frequent ventricular ectopy but no documented AF, also carried the mutation. Their mother and a maternal aunt were both diagnosed with early-onset AF and died suddenly during sleep at 60 and 55 years of age. QTc intervals in the sisters and their mother were normal. In the fourth family, an affected mother, daughter, and son were heterozygous for R231H. The mother had onset of paroxysmal AF at 32 years of age, and required cardioversion 10 times over the next 14 years to return to normal sinus rhythm. She had a normal QTc, and her older daughter, who developed AF at 16 years of age, also had a normal QTc. Her son, who had onset of paroxysmal AF at 13 years of age and also experienced significant bradycardia, had a prolonged QTc. A younger daughter was asymptomatic and did not carry the mutation.

Guerrier et al. (2013) reported a family in which the proband was a male infant with intermittent bradycardia, in whom ECG showed sinus bradycardia with normal intervals, including a QTc of 439 ms (upper limit of normal). QTc intervals on subsequent ECGs ranged between 392 and 439 ms. Echocardiogram showed normal cardiac anatomy. Family history revealed that his mother, maternal grandmother, and maternal great uncle had symptomatic atrial fibrillation, with diagnosis in the second or third decade of life, and the maternal great-great grandfather was also reported to have had an irregular heart rhythm. Symptoms included palpitations, dizziness, and fatigue; the grandmother and great uncle had undergone multiple cardioversion treatments, and the grandmother also had undergone ablation but continued to be symptomatic after the procedure. No family members had documented prolonged QT intervals, and there was no family history of sudden or unexplained death. Exercise testing in the proband's mother and asymptomatic 8-year-old brother revealed no repolarization abnormalities.

▼ Mapping
In a 4-generation Chinese family segregating autosomal dominant hereditary atrial fibrillation, Chen et al. (2003) found linkage of the disorder to chromosome 11p15.5 (maximum lod = 4.55 with no recombination at marker D11S4181).

In a 3-generation family with lone AF, Das et al. (2009) evaluated known genetic loci for AF as well as for other heritable conditions in which AF had been reported, and found evidence of linkage with marker DS11S4088, located within the KCNQ1 gene (lod score of 2.92 at theta = 0).

▼ Molecular Genetics
In all affected members of a Chinese family segregating autosomal dominant atrial fibrillation, Chen et al. (2003) identified a ser140-to-gly mutation (S140G; 607542.0032) in the KCNQ1 gene.

In a 3-generation family with lone AF mapping to chromosome 11p15, Das et al. (2009) identified heterozygosity for a missense mutation in KCNQ1 (S209P; 607542.0042). The mutation was incompletely penetrant, as 1 carrier individual with an affected child was unaffected both by history and by longitudinal ECG monitoring. Mutation carriers had a longer QRS duration, mild left ventricular dilation, and a trend toward larger left atrial dimension compared to noncarriers, but there was no difference in PR or corrected QT interval.

In a cohort of 231 patients with atrial fibrillation, Abraham et al. (2010) analyzed the KCNQ1 and NPPA (108780) genes and identified heterozygosity for a 9-bp duplication in KCNQ1 (607542.0041) in the proband of a Caucasian kindred segregating early-onset lone AF. The duplication was present in all 4 affected family members and in 2 symptomatic family members in whom AF had not yet been documented. It was not found in 3 unaffected family members or in Caucasian, Han Chinese, and Asian population controls; however, the duplication was detected in 2 (2.1%) of 94 African American control chromosomes that had been obtained from the anonymous Coriell repository, for which no clinical information was available. Abraham et al. (2010) also identified a missense mutation in the NPPA gene (108780.0002) in another AF family (ATFB6; 602201) in the cohort; functional analysis revealed strikingly similar gain-of-function defects associated with the mutants, with atrial action potential shortening and altered calcium current as a common mechanism.

Bartos et al. (2013) sequenced the candidate gene KCNQ1 in 4 families with early-onset AF (less than 40 years of age) and identified a missense mutation (R231H; 607542.0043) in affected individuals. The probands from 2 of the families were known to be negative for mutation in 5 other genes associated with autosomal dominant AF, including KCNH2 (152427), SCN5A (600163), KCNJ2 (600681), KCNE1 (176261), and KCNE2 (603796); the probands from the other 2 families were known to be negative for mutation in SCN5A. Bartos et al. (2013) noted that heterozygosity for the R231H mutation had been identified by Johnson et al. (2008) in a patient with both AF and a long QT interval (see 192500), but that the patient and her family were unavailable for study; the QTc interval was prolonged in only 1 of the 13 mutation-positive individuals from the 4 families studied by Bartos et al. (2013).

In a male infant with bradycardia and normal QT interval, Guerrier et al. (2013) identified heterozygosity for the R231H missense mutation in the KCNQ1 gene (R231H; 607542.0043). The mutation was also detected in 3 family members with atrial fibrillation as well as in the patient's asymptomatic 8-year-old brother. Guerrier et al. (2013) noted that the R231H mutation had previously been identified by Napolitano et al. (2005) in a study of patients with long QT syndrome (LQT1; 192500), but stated that none of the members of the family with atrial fibrillation had documented prolonged QT intervals.

Hasegawa et al. (2014) screened 30 patients with juvenile-onset AF for mutations in the KCNQ1, KCNH2, KCNE1, KCNE2, KCNE3 (604433), KCNE5 (300328), KCNJ2, and SCN5A genes, and identified heterozygosity for a missense mutation in KCNQ1 (G229D; 607542.0044) in a Japanese boy. He was diagnosed at 16 years of age with AF and a normal QT interval, and was later found to have borderline QT prolongation (QTc 452 ms to 480 ms). The mutation was also present in his asymptomatic mother, who also had borderline QT prolongation (QTc 468 ms). Functional analysis indicated that G229D causes constitutively open I(Ks) channels.

Tags: 11p15.5, 11p15.4