Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

Abstract

Transmission distortion of disease-causing alleles in long QT syndrome (LQTS) has been reported, suggesting a potential role of KCNQ1 and KCNH2 in reproduction. This study sought to investigate parental transmission in LQTS families according to ethnicity, gene loci (LQT1-3: KCNQ1, KCNH2, and SCN5A) or severity of channel dysfunction. We studied 3782 genotyped members from 679 European and Japanese LQTS families (2748 carriers). We determined grandparental and parental origins of variant alleles in 1903 children and 624 grandchildren, and the grandparental origin of normal alleles in healthy children from 44 three-generation control families. LQTS alleles were more of maternal than paternal origin (61 vs 39%, P<0.001). The ratio of maternally transmitted alleles in LQT1 (66%) was higher than in LQT2 (56%, P<0.001) and LQT3 (57%, P=0.03). Unlike the Mendelian distribution of grandparental alleles seen in control families, variant grandparental LQT1 and LQT2 alleles in grandchildren showed an excess of maternally transmitted grandmother alleles. For LQT1, maternal transmission differs according to the variant level of dysfunction with 68% of maternal transmission for dominant negative or unknown functional consequence variants vs 58% for non-dominant negative and variants leading to haploinsufficiency, P<0.01; however, for LQT2 or LQT3 this association was not significant. An excess of disease-causing alleles of maternal origin, most pronounced in LQT1, was consistently found across ethnic groups. This observation does not seem to be linked to an imbalance in transmission of the LQTS subtype-specific grandparental allele, but to the potential degree of potassium channel dysfunction.

Figure 1

Parental and grandparental origin of variant alleles in a LQT1 family. In this pedigree, there are 25 carriers (18 women) of the R555C variant including three obligate carriers. The classification of the variant carriers is illustrated by colored symbols. (a) Parental origin of LQTS alleles transmitted to carriers. (b) Grandparental origin of the LQTS alleles transmitted to the carriers. N, not tested. Proband is indicated by an arrow, and open circles and squares are non-carriers.

Figure 2

Parental origin of variant alleles transmitted to probands or all carriers for each LQTS subtype.

Figure 3

Grandparental origins of LQTS alleles for each LQT subtype. The upper bar shows the allele distribution of the four grandparental origins in CEPH families and the lower bar shows the variant-allele distribution of four grandparental origins in LQTS.

Figure 4

Parental origins of LQT1 alleles and channel dysfunction. LQT1 variants were classified as non-missense variants, leading to haploinsufficiency, non-dominant negative missense variants, and dominant negative missense variants when their co-expression with wild-type channels induced >50% reduction in I_Ks current according to published patch clamp analyses. The last group corresponds to variants with unknown functional consequences. The maternal transmission compared between the four function groups under the assumption that the four maternal transmission are equal to 0.5 was significantly different (P<0.0001). For more explanations on classification, see Supplementary Table S1.