Haskell Gloria T, Jensen Brian C, Skrzynia Cecile, Pulikkotil Thelsa, Tilley Christian R, Lu Yurong, Marchuk Daniel S, Ann Samsa Leigh, Wilhelmsen Kirk C, Lange Ethan, Patterson Cam, Evans James P, Berg Jonathan S
Department of Genetics, University of North Carolina at Chapel Hill, NC, USA. Electronic correspondence:
Department of Pharmacology, University of North Carolina at Chapel Hill, NC, USA.
J Heart Valve Dis. 2017 Sep;26(5):569-580.
A genetic component to familial mitral valve prolapse (MVP) has been proposed for decades. Despite this, very few genes have been linked to MVP. Herein is described a four-generation pedigree with numerous individuals affected with severe MVP, some at strikingly young ages.
A detailed clinical evaluation performed on all affected family members demonstrated a spectrum of MVP morphologies and associated phenotypes.
Linkage analysis failed to identify strong candidate loci, but revealed significant regions, which were investigated further using whole-exome sequencing of one of the severely affected family members. Whole-exome sequencing identified variants in this individual that fell within linkage analysis peak regions, but none was an obvious pathogenic candidate. Follow up segregation analysis of all exome-identified variants was performed to genotype other affected and unaffected individuals in the family, but no variants emerged as clear pathogenic candidates. Two notable variants of uncertain significance in candidate genes were identified: p.I1013S in PTPRJ at 11p11.2 and FLYWCH1 p.R540Q at 16p13.3. Neither gene has been previously linked to MVP in humans, although PTPRJ mutant mice display defects in endocardial cushions, which give rise to the cardiac valves. PTPRJ and FLYWCH1 expression was detected in adult human mitral valve cells, and in-silico analysis of these variants suggests they may be deleterious. However, neither variant segregated completely with all of the affected individuals in the family, particularly when 'affected' was broadly defined.
While a contributory role for PTPRJ and FLYWCH1 in this family cannot be excluded, the study results underscored the difficulties involved in uncovering the genomic contribution to MVP, even in apparently Mendelian families.
数十年来，人们一直认为家族性二尖瓣脱垂（MVP）存在遗传因素。尽管如此，与MVP相关的基因却非常少。本文描述了一个四代家系，其中有许多个体患有严重的MVP，有些患者发病年龄非常小。
对所有受影响的家庭成员进行了详细的临床评估，结果显示MVP存在一系列形态及相关表型。
连锁分析未能确定强有力的候选基因座，但发现了一些重要区域，随后对其中一名严重受影响的家庭成员进行全外显子测序以作进一步研究。全外显子测序在该个体中发现了位于连锁分析峰值区域内的变异，但没有一个是明显的致病候选基因。对所有外显子鉴定出的变异进行后续的分离分析，以确定该家族中其他受影响和未受影响个体的基因型，但没有变异显示为明确的致病候选基因。在候选基因中鉴定出两个意义不确定的显著变异：位于11p11.2的PTPRJ基因中的p.I1013S和位于16p13.3的FLYWCH1基因中的p.R540Q。此前，这两个基因在人类中均未与MVP相关联，尽管PTPRJ突变小鼠表现出心内膜垫缺陷，而心内膜垫会发育为心脏瓣膜。在成人二尖瓣细胞中检测到了PTPRJ和FLYWCH1的表达，对这些变异的计算机模拟分析表明它们可能具有有害性。然而，这两个变异在该家族的所有受影响个体中均未完全分离，尤其是在对“受影响”进行宽泛定义时。
虽然不能排除PTPRJ和FLYWCH1在这个家族中起作用，但研究结果强调了揭示MVP基因组贡献的困难，即使在看似符合孟德尔遗传模式的家族中也是如此。
