Partial uniparental isodisomy of chromosome 16 unmasks a deleterious biallelic mutation in IFT140 that causes Mainzer-Saldino syndrome.
Partial uniparental isodisomy of chromosome 16 unmasks a deleterious biallelic mutation in IFT140 that causes Mainzer-Saldino syndrome.
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DOI：
10.1186/s40246-017-0111-9
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发表时间：
2017-07-19
期刊：
影响因子：
4.5
通讯作者：
Davis EE
中科院分区：
文献类型：
--
作者：
Helm BM;Willer JR;Sadeghpour A;Golzio C;Crouch E;Vergano SS;Katsanis N;Davis EE
纤毛病代表了一个由>50种临床实体组成的伞状组，这些临床实体共享由初级纤毛的结构和功能缺陷所强调的临床特征和分子病因学。尽管基因发现取得了进展，但这组实体继续构成诊断挑战，部分原因是显著的遗传和表型异质性和变异性。我们咨询了一个无症状的非血缘父母的儿科病例，由于视网膜、肾脏和骨骼的一系列发现，他被怀疑为睫状体病。尽管肾病综合征相关基因的临床面板测序没有产生可能的因果突变，但寡核苷酸SNP微阵列在染色体16 p13上鉴定出约20 Mb的纯合性区域，没有改变基因剂量。交叉的先证者的表型与已知的疾病基因的纯合区域内产生了一个单一的候选人，IFFT 140，编码逆行鞭毛内转运蛋白牵连以前在几个纤毛病变，包括表型重叠的Mainzer-Saldino综合征（MPEDS）。桑格测序产生了一个母系遗传的纯合c.634 G>A; p.Gly212 Arg突变，改变了外显子6剪接供体位点。对先证者细胞的功能研究表明，该基因座产生了两种转录本：包含导致过早终止密码子的错误剪接事件的多数信息和p.Gly212Arg等位基因纯合的少数信息。后者的转录本的斑马鱼体内互补研究证明了功能丧失效应。最后，我们进行了事后基于trio的全外显子组测序研究，以（a）测试先证者中其他致病基因座的可能性和（B）解释IFFT 140突变的孟德尔分离错误。我们发现，先证者怀有16号染色体母系异二体性，在16 p13节段性等二体性，可能是由于减数分裂I错误的母系配子。使用临床表型结合基于研究的遗传和功能研究，我们已经确定了先证者的复发性IFT 140突变;总之，这些数据与MPEDS一致。此外，我们报告了一个罕见的情况下，单亲isodisomy揭露了有害的突变，导致睫状体疾病。本文的在线版本（doi：10.1186/s40246-017-0111-9）包含补充材料，可供授权用户使用。
The ciliopathies represent an umbrella group of >50 clinical entities that share both clinical features and molecular etiology underscored by structural and functional defects of the primary cilium. Despite the advances in gene discovery, this group of entities continues to pose a diagnostic challenge, in part due to significant genetic and phenotypic heterogeneity and variability. We consulted a pediatric case from asymptomatic, non-consanguineous parents who presented as a suspected ciliopathy due to a constellation of retinal, renal, and skeletal findings. Although clinical panel sequencing of genes implicated in nephrotic syndromes yielded no likely causal mutation, an oligo-SNP microarray identified a ~20-Mb region of homozygosity, with no altered gene dosage, on chromosome 16p13. Intersection of the proband’s phenotypes with known disease genes within the homozygous region yielded a single candidate, IFT140, encoding a retrograde intraflagellar transport protein implicated previously in several ciliopathies, including the phenotypically overlapping Mainzer-Saldino syndrome (MZSDS). Sanger sequencing yielded a maternally inherited homozygous c.634G>A; p.Gly212Arg mutation altering the exon 6 splice donor site. Functional studies in cells from the proband showed that the locus produced two transcripts: a majority message containing a mis-splicing event that caused a premature termination codon and a minority message homozygous for the p.Gly212Arg allele. Zebrafish in vivo complementation studies of the latter transcript demonstrated a loss of function effect. Finally, we conducted post-hoc trio-based whole exome sequencing studies to (a) test the possibility of other causal loci in the proband and (b) explain the Mendelian error of segregation for the IFT140 mutation. We show that the proband harbors a chromosome 16 maternal heterodisomy, with segmental isodisomy at 16p13, likely due to a meiosis I error in the maternal gamete. Using clinical phenotyping combined with research-based genetic and functional studies, we have characterized a recurrent IFT140 mutation in the proband; together, these data are consistent with MZSDS. Additionally, we report a rare instance of a uniparental isodisomy unmasking a deleterious mutation to cause a ciliary disorder. The online version of this article (doi:10.1186/s40246-017-0111-9) contains supplementary material, which is available to authorized users.
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DOI：
10.1038/nrg3493
发表时间：
2013-06
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.1
作者：
Bifari, Inam N.;Elkhamary, Sahar M.;Khan, Arif O.
通讯作者：
Khan, Arif O.
影响因子：
13.2
作者：
JENNETTE, JC;HIPP, CG
通讯作者：
HIPP, CG
影响因子：
30.8
作者：
Boute, N;Gribouval, O;Antignac, C
通讯作者：
Antignac, C
影响因子：
19.6
作者：
Hasselbacher, K.;Wiggins, R. C.;Hildebrandt, F.
通讯作者：
Hildebrandt, F.