PDF(Pubmed)
Abstract：
BACKGROUND: Congenital talipes equinovarus (CTEV) is a rotational foot deformity that affects muscles, bones, connective tissue, and vascular or neurological tissues. The etiology of CTEV is complex and unclear, involving genetic and environmental factors. Nail-patella syndrome is an autosomal dominant disorder caused by variants of the LIM homeobox transcription factor 1 beta gene (LMX1B, OMIM:602575). LMX1B plays a key role in the development of dorsal limb structures, the kidneys, and the eyes, and variants in this gene may manifest as hypoplastic or absent patella, dystrophic nails, and elbow and iliac horn dysplasia; glomerulopathy; and adult-onset glaucoma, respectively. This study aimed to identify pathogenic variants in a fetus with isolated talipes equinovarus diagnosed by ultrasound in the second trimester, whose father exhibited dysplastic nails and congenital absence of bilateral patella.
METHODS: Prenatal whole-exome sequencing (WES) of the fetus and parents was performed to identify the genetic variant responsible for the fetal ultrasound abnormality, followed by validation using Sanger sequencing.
RESULTS: A novel heterozygous nonsense variant in exon 6 of LMX1B (c.844C>T, p.Gln282*) was identified in the fetus and the affected father but was not detected in any unaffected family members. This nonsense variant resulted in a premature termination codon at position 282, which may be responsible for the clinical phenotype through the loss of function of the gene product.
CONCLUSIONS: Our study indicating that a fetus carrying a novel nonsense variant of LMX1B (c.844C>T, p.Gln282*) can exhibit isolated talipes equinovarus, which expands the LMX1B genotypic spectrum and is advantageous for genetic counseling.
METHODS: Prenatal whole-exome sequencing (WES) of the fetus and parents was performed to identify the genetic variant responsible for the fetal ultrasound abnormality, followed by validation using Sanger sequencing.
RESULTS: A novel heterozygous nonsense variant in exon 6 of LMX1B (c.844C>T, p.Gln282*) was identified in the fetus and the affected father but was not detected in any unaffected family members. This nonsense variant resulted in a premature termination codon at position 282, which may be responsible for the clinical phenotype through the loss of function of the gene product.
CONCLUSIONS: Our study indicating that a fetus carrying a novel nonsense variant of LMX1B (c.844C>T, p.Gln282*) can exhibit isolated talipes equinovarus, which expands the LMX1B genotypic spectrum and is advantageous for genetic counseling.
摘要：
背景：先天性马蹄内翻足（CTEV）是一种影响肌肉的旋转足畸形，骨头,结缔组织,和血管或神经组织。CTEV的病因复杂且不明确,涉及遗传和环境因素。指甲髌骨综合征是由LIM同源异型盒转录因子1β基因变异引起的常染色体显性遗传病（LMX1B，OMIM：602575）。LMX1B在后肢结构的发育中起着关键作用，肾脏，和眼睛，这个基因的变异可能表现为髌骨发育不全或缺失，营养不良的指甲，和肘和髂角发育不良;肾小球病;和成人发作性青光眼，分别。这项研究旨在确定在妊娠中期通过超声诊断出的孤立性马蹄内翻足胎儿的致病变异，其父亲表现出发育不良的指甲和先天性双侧髌骨缺失。
方法：对胎儿和父母进行产前全外显子组测序（WES），以确定导致胎儿超声异常的遗传变异，然后使用Sanger测序进行验证。
结果：LMX1B外显子6中的一种新型杂合无义变体（c.844C>T，在胎儿和受影响的父亲中鉴定出p.Gln282*），但在任何未受影响的家庭成员中均未检测到。该无义变体在位置282处导致过早终止密码子,其可能通过基因产物功能的丧失而导致临床表型。
结论：我们的研究表明，胎儿携带LMX1B的新型无义变体（c.844C>T，p.Gln282*)可以表现出孤立的马蹄内翻足，这扩展了LMX1B基因型谱，有利于遗传咨询。
方法：对胎儿和父母进行产前全外显子组测序（WES），以确定导致胎儿超声异常的遗传变异，然后使用Sanger测序进行验证。
结果：LMX1B外显子6中的一种新型杂合无义变体（c.844C>T，在胎儿和受影响的父亲中鉴定出p.Gln282*），但在任何未受影响的家庭成员中均未检测到。该无义变体在位置282处导致过早终止密码子,其可能通过基因产物功能的丧失而导致临床表型。
结论：我们的研究表明，胎儿携带LMX1B的新型无义变体（c.844C>T，p.Gln282*)可以表现出孤立的马蹄内翻足，这扩展了LMX1B基因型谱，有利于遗传咨询。
