一个具有多种先天性泌尿生殖系统畸形的家族中分离的新的遗传性CDX2变体。

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Cold Spring Harbor Molecular Case Studies Pub Date : 2024-01-10 Print Date: 2023-12-01 DOI:10.1101/mcs.a006294
Swetha Ramadesikan, Caitlyn M Colwell, Rachel Supinger, Jesse Hunter, Jessica Thomas, Elizabeth Varga, Elaine R Mardis, Richard J Wood, Daniel C Koboldt
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引用次数: 0

摘要

肛门直肠畸形(ARM)是一组先天性胃肠和泌尿生殖系统缺陷。它们影响男性和女性,估计全世界每5000名活产婴儿中就有1人患病。这些畸形在临床上是异质性的,可以是综合征表现(综合征性ARM)的一部分,也可以是非综合征实体(非综合征性ARM)。尽管公认的非综合征ARM的遗传性,但大多数患者的遗传病因尚不清楚。在这项研究中,我们描述了三个患有不同先天性泌尿生殖系统异常、贫血、里程碑延迟和骨骼异常的兄弟姐妹。全基因组测序确定了一种新的父系遗传杂合CDX2变体(c.722A>G(p.Glu241Gly)),该变体存在于所有3个受影响的兄弟姐妹中。在该家族中鉴定出的变体没有出现在人群数据库中,并被大多数计算机致病性工具预测为具有破坏性。到目前为止,只有2份其他报告涉及CDX2与ARM的变体。值得注意的是,这些研究中描述的患者在CDX2中表现出相似的临床表型和基因改变。CDX2编码一种转录因子,被认为是胃肠道发育的主要调节因子。该变体映射到编码蛋白质的同源框结构域,这对于与DNA靶标的相互作用至关重要。我们的发现为我们家族的病情提供了一种潜在的分子诊断,并支持CDX2在肛门直肠异常中的作用。它还强调了ARM易感性变异的临床异质性和可变外显率,这是另一个有充分记录的现象。最后,它强调了ARM基因组图谱在确定这些缺陷的遗传病因方面的诊断实用性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Novel inherited CDX2 variant segregating in a family with diverse congenital malformations of the genitourinary system.

Anorectal malformations (ARMs) constitute a group of congenital defects of the gastrointestinal and urogenital systems. They affect males and females, with an estimated worldwide prevalence of 1 in 5000 live births. These malformations are clinically heterogeneous and can be part of a syndromic presentation (syndromic ARM) or as a nonsyndromic entity (nonsyndromic ARM). Despite the well-recognized heritability of nonsyndromic ARM, the genetic etiology in most patients is unknown. In this study, we describe three siblings with diverse congenital anomalies of the genitourinary system, anemia, delayed milestones, and skeletal anomalies. Genome sequencing identified a novel, paternally inherited heterozygous Caudal type Homeobox 2 (CDX2) variant (c.722A > G (p.Glu241Gly)), that was present in all three affected siblings. The variant identified in this family is absent from population databases and predicted to be damaging by most in silico pathogenicity tools. So far, only two other reports implicate variants in CDX2 with ARMs. Remarkably, the individuals described in these studies had similar clinical phenotypes and genetic alterations in CDX2 CDX2 encodes a transcription factor and is considered the master regulator of gastrointestinal development. This variant maps to the homeobox domain of the encoded protein, which is critical for interaction with DNA targets. Our finding provides a potential molecular diagnosis for this family's condition and supports the role of CDX2 in anorectal anomalies. It also highlights the clinical heterogeneity and variable penetrance of ARM predisposition variants, another well-documented phenomenon. Finally, it underscores the diagnostic utility of genomic profiling of ARMs to identify the genetic etiology of these defects.

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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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