Abstract：
BACKGROUND: Hand-Foot-Genital Syndrome (HFGS) is an autosomal dominant disorder characterized by a broad phenotypic spectrum. Variants in HOXA13 gene were associated with HFGS. To date, only twenty families with HFGS have been reported. However, the challenge in HFGS is the limited sample sizes and phenotypic heterogeneity. The advent of next-generation sequencing has permitted the identification of patients with HOXA13 variants who do not manifest with the full HFGS syndromic features.
METHODS: Trio (parents-proband) Whole-exome sequence(WES) and whole-genome sequencing(WGS) was carried out in this study to investigate the underlying pathogenic genetic factor of the neonate with a wide variety of clinical abnormalities.
RESULTS: No possible pathogenetic variation was detected by trio-WES, and a duplication variant in HOXA13 (c.360_377dup, p.Ala128_Ala133dup), inherited from her mother, was identified by the subsequent WGS in the proband with malnutrition, feeding difficulties, electrolyte disorders, metabolic acidosis, recurrent urinary tract infections, hydronephrosis, nephrolithiasis, abnormal ureter morphology, cholelithiasis, uterus didelphys. Sequence analysis of the variant region (exon1) indicated a high GC content of 73.92%. In addition, further enquiry of the family history revealed that 5 members of the family in 4 generations had hand and foot anomalies.
CONCLUSIONS: The neonate was diagnosed with HFGS by genetic analysis. GC content had less influence on sequence coverage in WGS than WES analysis. This was the first report of trio-WGS study for HFGS genetic diagnosis, revealed that subsequent WGS was necessary for identification of potentially pathogenic variants in unexplained genetic disorders.
METHODS: Trio (parents-proband) Whole-exome sequence(WES) and whole-genome sequencing(WGS) was carried out in this study to investigate the underlying pathogenic genetic factor of the neonate with a wide variety of clinical abnormalities.
RESULTS: No possible pathogenetic variation was detected by trio-WES, and a duplication variant in HOXA13 (c.360_377dup, p.Ala128_Ala133dup), inherited from her mother, was identified by the subsequent WGS in the proband with malnutrition, feeding difficulties, electrolyte disorders, metabolic acidosis, recurrent urinary tract infections, hydronephrosis, nephrolithiasis, abnormal ureter morphology, cholelithiasis, uterus didelphys. Sequence analysis of the variant region (exon1) indicated a high GC content of 73.92%. In addition, further enquiry of the family history revealed that 5 members of the family in 4 generations had hand and foot anomalies.
CONCLUSIONS: The neonate was diagnosed with HFGS by genetic analysis. GC content had less influence on sequence coverage in WGS than WES analysis. This was the first report of trio-WGS study for HFGS genetic diagnosis, revealed that subsequent WGS was necessary for identification of potentially pathogenic variants in unexplained genetic disorders.
摘要：
背景：手足生殖器综合征（HFGS）是一种常染色体显性遗传疾病，其特征是具有广泛的表型谱。HOXA13基因变异与HFGS相关。迄今为止,据报道，只有20个家庭患有HFGS。然而,HFGS的挑战是有限的样本量和表型异质性.下一代测序的出现允许鉴定HOXA13变异的患者，这些患者没有表现出完整的HFGS综合征特征。
方法：本研究进行了Trio（父母先证者）全外显子组测序（WES）和全基因组测序（WGS），以研究具有多种临床异常的新生儿的潜在致病遗传因素。
结果：Trio-WES未检测到可能的致病变异，和HOXA13中的重复变体(c.360_377dup，p.Ala128_Ala133dup)，从她母亲那里继承下来,随后的WGS在先证者中发现营养不良，喂养困难，电解质紊乱,代谢性酸中毒,复发性尿路感染，肾积水,肾结石,输尿管形态异常，胆石症,子宫didelphys。变异区(外显子1)的序列分析表明73.92%的高GC含量。此外,对家族史的进一步调查显示，该家族4代中有5名成员有手脚异常。
结论：通过基因分析，新生儿被诊断为HFGS。与WES分析相比，GC含量对WGS中序列覆盖率的影响较小。这是用于HFGS基因诊断的Trio-WGS研究的第一份报告，揭示了随后的WGS对于鉴定无法解释的遗传疾病中的潜在致病变异是必要的。
方法：本研究进行了Trio（父母先证者）全外显子组测序（WES）和全基因组测序（WGS），以研究具有多种临床异常的新生儿的潜在致病遗传因素。
结果：Trio-WES未检测到可能的致病变异，和HOXA13中的重复变体(c.360_377dup，p.Ala128_Ala133dup)，从她母亲那里继承下来,随后的WGS在先证者中发现营养不良，喂养困难，电解质紊乱,代谢性酸中毒,复发性尿路感染，肾积水,肾结石,输尿管形态异常，胆石症,子宫didelphys。变异区(外显子1)的序列分析表明73.92%的高GC含量。此外,对家族史的进一步调查显示，该家族4代中有5名成员有手脚异常。
结论：通过基因分析，新生儿被诊断为HFGS。与WES分析相比，GC含量对WGS中序列覆盖率的影响较小。这是用于HFGS基因诊断的Trio-WGS研究的第一份报告，揭示了随后的WGS对于鉴定无法解释的遗传疾病中的潜在致病变异是必要的。
