Rare metabolic disease mimicking COL4A1/COL4A2 fetal brain phenotype.
Rare metabolic disease mimicking COL4A1/COL4A2 fetal brain phenotype.
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DOI：
10.1002/uog.26046
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发表时间：
2022-12
影响因子：
7.1
通讯作者：
Tournier-Lasserve, E.
中科院分区：
文献类型：
--
作者：
Coste, T.;Aloui, C.;Petit, F.;Moutton, S.;Devisme, L.;Wells, C. F.;Leboucq, N.;Verpillat, P.;Yvert, M.;Rivier, F.;Tournier-Lasserve, E.
IV型胶原α1和2(COL4A1/COL4A2)基因的致病变异可导致多种表型异常，包括脑出血和广泛的发育异常。在接受COL4A1/COL4A2分子筛查的胎儿(疑似脑出血的胎儿)中，只有20%携带这些基因的致病变异，这引发了对其余80%胎儿致病异常的疑问。在终止妊娠或胎儿宫内死亡后，我们检查了一系列进行COL4A1/COL4A2分子筛查的无关胎儿，其中靶向测序为阴性。利用外显子组测序数据和基于基因的折叠试验，我们在我们的胎儿队列中寻找与基因组聚合数据库(GnomAD)对照队列(n=71702)相比的罕见合格变异的丰富。在我们的队列中，丙酮酸脱氢酶E1亚单位α1(PDHA1)的合格变异过高，达到全基因组意义(P=2.11×10−7)。在三个女性胎儿中发现了杂合性PDHA1功能丧失变异体。在这三个病例中，我们观察到小头畸形、脑室增大、生殖细胞溶解的假性囊肿、胼胝体发育不全/发育不良和白质异常，这些最初提示脑缺氧缺血和出血性损害。然而，仔细的影像和尸检数据的事后再分析表明，观察到的损害也与携带PDHA1致病变异体的胎儿观察到的一致，强烈表明这两种表型可能重叠。因此，应对筛查阴性的COL4A1/COL4A2分子筛查的胎儿进行外显子组测序，并特别注意PDHA1基因。
Pathogenic variants of collagen type IV alpha 1 and 2 (COL4A1/COL4A2) genes cause various phenotypic anomalies, including intracerebral hemorrhage and a wide spectrum of developmental anomalies. Only 20% of fetuses referred for COL4A1/COL4A2 molecular screening (fetuses with a suspected intracerebral hemorrhage) carry a pathogenic variant in these genes, raising questions regarding the causative anomaly in the remaining 80% of these fetuses. We examined, following termination of pregnancy or in-utero fetal death, a series of 113 unrelated fetuses referred for COL4A1/COL4A2 molecular screening, in which targeted sequencing was negative. Using exome sequencing data and a gene-based collapsing test, we searched for enrichment of rare qualifying variants in our fetal cohort in comparison to the Genome Aggregation Database (gnomAD) control cohort (n = 71702). Qualifying variants in pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) were overrepresented in our cohort, reaching genome-wide significance (P = 2.11 × 10−7). Heterozygous PDHA1 loss-of-function variants were identified in three female fetuses. Among these three cases, we observed microcephaly, ventriculomegaly, germinolytic pseudocysts, agenesis/dysgenesis of the corpus callosum and white-matter anomalies that initially suggested cerebral hypoxic-ischemic and hemorrhagic lesions. However, a careful a-posteriori reanalysis of imaging and postmortem data showed that the observed lesions were also consistent with those observed in fetuses carrying PDHA1 pathogenic variants, strongly suggesting that these two phenotypes may overlap. Exome sequencing should therefore be performed in fetuses referred for COL4A1/COL4A2 molecular screening which are screen-negative, with particular attention paid to the PDHA1 gene.
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