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Article

Fine Breakpoint Mapping by Genome Sequencing Reveals the First Large X Inversion Disrupting the NHS Gene in a Patient with Syndromic Cataracts

1
Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain
2
Centre for Biomedical Network Research on Rare Diseases (CIBERER), 28290 Madrid, Spain
3
Department of Medical Genetics, University Hospital Clínico San Carlos, 28040 Madrid, Spain
4
Department of Pediatrics, University Hospital Clínico San Carlos, 28040 Madrid, Spain
5
Bioinformatics Unit, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28040, Madrid, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Murat Dogru
Int. J. Mol. Sci. 2021, 22(23), 12713; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312713
Received: 29 September 2021 / Revised: 17 November 2021 / Accepted: 19 November 2021 / Published: 24 November 2021
(This article belongs to the Special Issue Structural Variations of the Genome)
Inversions are structural variants that are generally balanced. However, they could lead to gene disruptions or have positional effects leading to diseases. Mutations in the NHS gene cause Nance-Horan syndrome, an X-linked disorder characterised by congenital cataracts and dental anomalies. Here, we aimed to characterise a balanced pericentric inversion X(p22q27), maternally inherited, in a child with syndromic bilateral cataracts by breakpoint mapping using whole-genome sequencing (WGS). 30× Illumina paired-end WGS was performed in the proband, and breakpoints were confirmed by Sanger sequencing. EdU assays and FISH analysis were used to assess skewed X-inactivation patterns. RNA expression of involved genes in the breakpoint boundaries was evaluated by droplet-digital PCR. We defined the breakpoint position of the inversion at Xp22.13, with a 15 bp deletion, disrupting the unusually large intron 1 of the canonical NHS isoform, and also perturbing topologically-associated domains (TADs). Moreover, a microhomology region of 5 bp was found on both sides. RNA analysis confirmed null and reduced NHS expression in the proband and his unaffected mother, respectively. In conclusion, we report the first chromosomal inversion disrupting NHS, fine-mapped by WGS. Our data expand the clinical spectrum and the pathogenic mechanisms underlying the NHS defects. View Full-Text
Keywords: congenital cataract; pericentric X inversion; NHS; Nance-Horan syndrome; structural variation (SV); whole-genome sequencing (WGS); chromosomal rearrangement; topologically associated domains (TADs); position effects congenital cataract; pericentric X inversion; NHS; Nance-Horan syndrome; structural variation (SV); whole-genome sequencing (WGS); chromosomal rearrangement; topologically associated domains (TADs); position effects
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MDPI and ACS Style

Damián, A.; Ionescu, R.O.; Rodríguez de Alba, M.; Tamayo, A.; Trujillo-Tiebas, M.J.; Cotarelo-Pérez, M.C.; Pérez Rodríguez, O.; Villaverde, C.; de la Fuente, L.; Romero, R.; Núñez-Moreno, G.; Mínguez, P.; Ayuso, C.; Cortón, M. Fine Breakpoint Mapping by Genome Sequencing Reveals the First Large X Inversion Disrupting the NHS Gene in a Patient with Syndromic Cataracts. Int. J. Mol. Sci. 2021, 22, 12713. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312713

AMA Style

Damián A, Ionescu RO, Rodríguez de Alba M, Tamayo A, Trujillo-Tiebas MJ, Cotarelo-Pérez MC, Pérez Rodríguez O, Villaverde C, de la Fuente L, Romero R, Núñez-Moreno G, Mínguez P, Ayuso C, Cortón M. Fine Breakpoint Mapping by Genome Sequencing Reveals the First Large X Inversion Disrupting the NHS Gene in a Patient with Syndromic Cataracts. International Journal of Molecular Sciences. 2021; 22(23):12713. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312713

Chicago/Turabian Style

Damián, Alejandra, Raluca O. Ionescu, Marta Rodríguez de Alba, Alejandra Tamayo, María J. Trujillo-Tiebas, María C. Cotarelo-Pérez, Olga Pérez Rodríguez, Cristina Villaverde, Lorena de la Fuente, Raquel Romero, Gonzalo Núñez-Moreno, Pablo Mínguez, Carmen Ayuso, and Marta Cortón. 2021. "Fine Breakpoint Mapping by Genome Sequencing Reveals the First Large X Inversion Disrupting the NHS Gene in a Patient with Syndromic Cataracts" International Journal of Molecular Sciences 22, no. 23: 12713. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312713

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