Abstract：
Thirteen affected individuals of six generations of a single kindred presented with epiphora evident from infancy. Physical exam and Schirmer test revealed variable expression of tear deficiency, congenital punctal atresia, and dry mouth with multiple caries, without concomitant abnormalities of the ears or digits, commensurate with a diagnosis of aplasia of the lacrimal and salivary glands (ALSG). Reconstruction of the upper lacrimal drainage system was performed in some of the affected individuals. Genetic analysis, testing six affected individuals and three non-affected family members, identified a single novel heterozygous splice-site variant, c.429 + 1, G > T in fibroblast growth factor 10 (FGF10) (NM_004465.1), segregating throughout the family as expected for dominant heredity. RT-PCR assays of HEK-293 cells transfected with wild type or mutant FGF10 demonstrated that the variant causes skipping of Exon 2. Notably, individuals sharing the same variant exhibited phenotypic variability, with unilateral or bilateral epiphora, as well as variable expression of dry mouth and caries. Moreover, one of the variant carriers had no ALSG-related clinical findings, demonstrating incomplete penetrance. While coding mutations in FGF10 are known to cause malformations in the nasolacrimal system, this is the second FGF10 splice-site variant and the first donor-site variant reported to cause ALSG. Thus, our study of a unique large kindred with multiple affected individuals heterozygous for the same FGF10 variant highlights intronic splice-site mutations and phenotypic variability/partial penetrance in ALSG.
摘要：
从婴儿期开始，六代单亲的十三个受影响的个体表现出明显的顿裂。体格检查和Schirmer测试显示泪液缺乏的可变表达，先天性泪点闭锁,口干有多个龋齿，没有伴随的耳朵或手指异常，与泪腺和唾液腺发育不全（ALSG）的诊断相称。在一些受影响的个体中进行了上泪道引流系统的重建。基因分析,测试六名受影响的个人和三名未受影响的家庭成员，鉴定了一个新的杂合剪接位点变体，c.429+1，成纤维细胞生长因子10（FGF10）（NM_004465.1）中G>T，在整个家庭中分离，如预期的显性遗传。用野生型或突变型FGF10转染的HEK-293细胞的RT-PCR测定表明该变体导致外显子2的跳跃。值得注意的是,共享相同变异的个体表现出表型变异性，有单侧或双侧顿唇，以及口干和龋齿的可变表达。此外，其中一个变异携带者没有ALSG相关的临床表现，显示不完整的外显率。虽然已知FGF10的编码突变会导致鼻泪系统畸形，这是第二个FGF10剪接位点变异体,也是据报道导致ALSG的第一个供体位点变异体.因此，我们对同一FGF10变体的多个受影响个体杂合的独特大型家族的研究强调了ALSG中内含子剪接位点突变和表型变异性/部分外显率。
