Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH.
Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH.
复制标题
临床外显子组测序数据显示，先天性膈疝合并其他异常（CDH+）的诊断率较高，且发现了涉及先天性膈疝的新表型扩展。
DOI：
10.1136/jmedgenet-2020-107317
复制
发表时间：
2022-03
影响因子：
4
通讯作者：
Scott DA
中科院分区：
文献类型：
--
作者：
Scott TM;Campbell IM;Hernandez-Garcia A;Lalani SR;Liu P;Shaw CA;Rosenfeld JA;Scott DA
先天性腹股沟疝（CDH）是一种危及生命的出生缺陷，通常与非疝相关异常（CDH+）同时发生。虽然拷贝数变异（CNV）分析经常被用作CDH+的诊断测试，但临床外显子组测序（ES）尚未被普遍采用。我们分析了约12，000个测试结果的临床数据库，以确定CDH+外显子组测序的诊断产率，并确定新的表型扩增。在76例CDH阳性患者中，28例进行了分子诊断，诊断率为37%（28/76）。另有7例（9%; 7/76）作出临时诊断。4名患者被诊断为KMT 2D移码变异引起的歌舞伎综合征。在ALG 12和EP 300中的脓毒症有害变体分别在两个个体中发现，支持它们在CDH发展中的作用。我们还鉴定了FOXP 1和SMARCA 4中具有新发致病性变异的个体，以及BRCA 2中具有复合杂合致病性变异的个体。这些基因在CDH发展中的作用得到了其小鼠同源物在发育中的横膈膜中表达的支持，其高CDH特异性致病性评分使用先前验证的基因组规模知识合成算法和先前发表的病例报告产生。我们的结论是，ES应下令在CDH+的情况下，当一个特定的诊断是不怀疑和CNV分析是阴性的。我们的研究结果还提供了证据，有利于表型扩增涉及CDH的基因与ALG 12-先天性糖基化疾病，Rubinstein-Taybi综合征，范科尼贫血，Coffin-Siris综合征和FOXP 1相关的疾病。
Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted. We analyzed a clinical database of ~12,000 test results to determine the diagnostic yields of exome sequencing in CDH+ and to identify new phenotypic expansions. Among the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other cases (9%; 7/76). Four individuals had a diagnosis of Kabuki syndrome caused by frameshift variants in KMT2D. Putatively deleterious variants in ALG12 and EP300 were each found in two individuals, supporting their role in CDH development. We also identified individuals with de novo pathogenic variants in FOXP1 and SMARCA4, and compound heterozygous pathogenic variants in BRCA2. The role of these genes in CDH development is supported by the expression of their mouse homologs in the developing diaphragm, their high CDH-specific pathogenicity scores generated using a previously validated algorithm for genome-scale knowledge synthesis, and previously published case reports. We conclude that ES should be ordered in cases of CDH+ when a specific diagnosis is not suspected and CNV analyses are negative. Our results also provide evidence in favor of phenotypic expansions involving CDH for genes associated with ALG12-congenital disorder of glycosylation, Rubinstein-Taybi syndrome, Fanconi anemia, Coffin-Siris syndrome and FOXP1-related disorders.
登录
查看更多内容
DOI：
10.1038/gim.2016.131
发表时间：
2017-04
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Bekheirnia MR;Bekheirnia N;Bainbridge MN;Gu S;Coban Akdemir ZH;Gambin T;Janzen NK;Jhangiani SN;Muzny DM;Michael M;Brewer ED;Elenberg E;Kale AS;Riley AA;Swartz SJ;Scott DA;Yang Y;Srivaths PR;Wenderfer SE;Bodurtha J;Applegate CD;Velinov M;Myers A;Borovik L;Craigen WJ;Hanchard NA;Rosenfeld JA;Lewis RA;Gonzales ET;Gibbs RA;Belmont JW;Roth DR;Eng C;Braun MC;Lupski JR;Lamb DJ
通讯作者：
Lamb DJ
影响因子：
3.5
作者：
Longoni M;Russell MK;High FA;Darvishi K;Maalouf FI;Kashani A;Tracy AA;Coletti CM;Loscertales M;Lage K;Ackerman KG;Woods SA;Ward-Melver C;Andrews D;Lee C;Pober BR;Donahoe PK
通讯作者：
Donahoe PK
影响因子：
4.6
作者：
Gray, Brian W.;Fifer, Carlen G.;Kunisaki, Shaun M.
通讯作者：
Kunisaki, Shaun M.
影响因子：
1.9
作者：
Matias, Margret;Wusik, Katie;Collins, Kathleen
通讯作者：
Collins, Kathleen
影响因子：
3.6
作者：
Milani D;Manzoni FM;Pezzani L;Ajmone P;Gervasini C;Menni F;Esposito S
通讯作者：
Esposito S