Tags

Type your tag names separated by a space and hit enter

Identification of compound heterozygous variants in the noncoding RNU4ATAC gene in a Chinese family with two successive foetuses with severe microcephaly.
Hum Genomics 2018; 12(1):3HG

Abstract

BACKGROUND

Whole-exome sequencing (WES) over the last few years has been increasingly employed for clinical diagnosis. However, one caveat with its use is that it inevitably fails to detect disease-causative variants that occur within noncoding RNA genes. Our experience in identifying pathogenic variants in the noncoding RNU4ATAC gene, in a Chinese family where two successive foetuses had been affected by severe microcephaly, is a case in point. These foetuses exhibited remarkably similar phenotypes in terms of their microcephaly and brain abnormalities; however, the paucity of other characteristic phenotypic features had made a precise diagnosis impossible. Given that no external causative factors had been reported/identified during the pregnancies, we sought a genetic cause for the phenotype in the proband, the second affected foetus.

RESULTS

A search for chromosomal abnormalities and pathogenic copy number variants proved negative. WES was also negative. These initial failures prompted us to consider the potential role of RNU4ATAC, a noncoding gene implicated in microcephalic osteodysplastic primordial dwarfism type-1 (MOPD1), a severe autosomal recessive disease characterised by dwarfism, severe microcephaly and neurological abnormalities. Subsequent targeted sequencing of RNU4ATAC resulted in the identification of compound heterozygous variants, one being the most frequently reported MOPD1-causative mutation (51G>A), whereas the other was a novel 29T>A variant. Four distinct lines of evidence (allele frequency in normal populations, evolutionary conservation of the affected nucleotide, occurrence within a known mutational hotspot for MOPD1-causative variants and predicted effect on RNA secondary structure) allowed us to conclude that 29T>A is a new causative variant for MOPD1.

CONCLUSIONS

Our findings highlight the limitations of WES in failing to detect variants within noncoding RNA genes and provide support for a role for whole-genome sequencing as a first-tier genetic test in paediatric medicine. Additionally, the identification of a novel RNU4ATAC variant within the mutational hotspot for MOPD1-causative variants further strengthens the critical role of the 5' stem-loop structure of U4atac in health and disease. Finally, this analysis enabled us to provide prenatal diagnosis and genetic counselling for the mother's third pregnancy, the first report of its kind in the context of inherited RNU4ATAC variants.

Authors+Show Affiliations

Fetal Medicine Centre, Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou, China.Department of Ultrasonic Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.Department of Ultrasonic Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.Fetal Medicine Centre, Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.Guangzhou KingMed Center for Clinical Laboratory, Guangzhou, China.Dongguan Women and Children's Hospital, Dongguan, China.Department of Ultrasonic Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.UMR1078 "Génétique, Génomique Fonctionnelle et Biotechnologies", INSERM, EFS - Bretagne, Université de Brest, CHRU Brest, Brest, France.Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK.Fetal Medicine Centre, Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. luoyanm@mail.sysu.edu.cn.Fetal Medicine Centre, Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. fang_qun@163.com.UMR1078 "Génétique, Génomique Fonctionnelle et Biotechnologies", INSERM, EFS - Bretagne, Université de Brest, CHRU Brest, Brest, France. jian-min.chen@univ-brest.fr. INSERM UMR1078, EFS, UBO, 22 avenue Camille Desmoulins, 29238, Brest, France. jian-min.chen@univ-brest.fr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29370840

Citation

Wang, Ye, et al. "Identification of Compound Heterozygous Variants in the Noncoding RNU4ATAC Gene in a Chinese Family With Two Successive Foetuses With Severe Microcephaly." Human Genomics, vol. 12, no. 1, 2018, p. 3.
Wang Y, Wu X, Du L, et al. Identification of compound heterozygous variants in the noncoding RNU4ATAC gene in a Chinese family with two successive foetuses with severe microcephaly. Hum Genomics. 2018;12(1):3.
Wang, Y., Wu, X., Du, L., Zheng, J., Deng, S., Bi, X., ... Chen, J. M. (2018). Identification of compound heterozygous variants in the noncoding RNU4ATAC gene in a Chinese family with two successive foetuses with severe microcephaly. Human Genomics, 12(1), p. 3. doi:10.1186/s40246-018-0135-9.
Wang Y, et al. Identification of Compound Heterozygous Variants in the Noncoding RNU4ATAC Gene in a Chinese Family With Two Successive Foetuses With Severe Microcephaly. Hum Genomics. 2018 01 25;12(1):3. PubMed PMID: 29370840.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of compound heterozygous variants in the noncoding RNU4ATAC gene in a Chinese family with two successive foetuses with severe microcephaly. AU - Wang,Ye, AU - Wu,Xueli, AU - Du,Liu, AU - Zheng,Ju, AU - Deng,Songqing, AU - Bi,Xin, AU - Chen,Qiuyan, AU - Xie,Hongning, AU - Férec,Claude, AU - Cooper,David N, AU - Luo,Yanmin, AU - Fang,Qun, AU - Chen,Jian-Min, Y1 - 2018/01/25/ PY - 2017/12/29/received PY - 2018/01/17/accepted PY - 2018/1/27/entrez PY - 2018/1/27/pubmed PY - 2019/2/1/medline KW - Genetic counselling KW - MOPD1 KW - Microcephalic osteodysplastic primordial dwarfism type 1 KW - Noncoding RNU4ATAC gene KW - Prenatal diagnosis KW - RNA secondary structure KW - Small nuclear RNA KW - Taybi-Linder syndrome KW - WES KW - Whole-exome sequencing SP - 3 EP - 3 JF - Human genomics JO - Hum. Genomics VL - 12 IS - 1 N2 - BACKGROUND: Whole-exome sequencing (WES) over the last few years has been increasingly employed for clinical diagnosis. However, one caveat with its use is that it inevitably fails to detect disease-causative variants that occur within noncoding RNA genes. Our experience in identifying pathogenic variants in the noncoding RNU4ATAC gene, in a Chinese family where two successive foetuses had been affected by severe microcephaly, is a case in point. These foetuses exhibited remarkably similar phenotypes in terms of their microcephaly and brain abnormalities; however, the paucity of other characteristic phenotypic features had made a precise diagnosis impossible. Given that no external causative factors had been reported/identified during the pregnancies, we sought a genetic cause for the phenotype in the proband, the second affected foetus. RESULTS: A search for chromosomal abnormalities and pathogenic copy number variants proved negative. WES was also negative. These initial failures prompted us to consider the potential role of RNU4ATAC, a noncoding gene implicated in microcephalic osteodysplastic primordial dwarfism type-1 (MOPD1), a severe autosomal recessive disease characterised by dwarfism, severe microcephaly and neurological abnormalities. Subsequent targeted sequencing of RNU4ATAC resulted in the identification of compound heterozygous variants, one being the most frequently reported MOPD1-causative mutation (51G>A), whereas the other was a novel 29T>A variant. Four distinct lines of evidence (allele frequency in normal populations, evolutionary conservation of the affected nucleotide, occurrence within a known mutational hotspot for MOPD1-causative variants and predicted effect on RNA secondary structure) allowed us to conclude that 29T>A is a new causative variant for MOPD1. CONCLUSIONS: Our findings highlight the limitations of WES in failing to detect variants within noncoding RNA genes and provide support for a role for whole-genome sequencing as a first-tier genetic test in paediatric medicine. Additionally, the identification of a novel RNU4ATAC variant within the mutational hotspot for MOPD1-causative variants further strengthens the critical role of the 5' stem-loop structure of U4atac in health and disease. Finally, this analysis enabled us to provide prenatal diagnosis and genetic counselling for the mother's third pregnancy, the first report of its kind in the context of inherited RNU4ATAC variants. SN - 1479-7364 UR - https://www.unboundmedicine.com/medline/citation/29370840/Identification_of_compound_heterozygous_variants_in_the_noncoding_RNU4ATAC_gene_in_a_Chinese_family_with_two_successive_foetuses_with_severe_microcephaly_ L2 - https://humgenomics.biomedcentral.com/articles/10.1186/s40246-018-0135-9 DB - PRIME DP - Unbound Medicine ER -