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

• Published in: International journal of molecular sciences Vol. 22; no. 23; p. 12713
• Main Authors: Damián, Alejandra, Ionescu, Raluca Oancea, Rodríguez de Alba, Marta, Tamayo, Alejandra, Trujillo-Tiebas, María José, Cotarelo-Pérez, María Carmen, Pérez Rodríguez, Olga, Villaverde, Cristina, de la Fuente, Lorena, Romero, Raquel, Núñez-Moreno, Gonzalo, Mínguez, Pablo, Ayuso, Carmen, Cortón, Marta
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24-11-2021; MDPI
• Subjects: Anomalies; Breakpoints; Cataract - congenital; Cataract - etiology; Cataract - metabolism; Cataract - pathology; Cataracts; Child; Chromosome Breakpoints; Chromosome Inversion; Chromosome Mapping; Chromosome rearrangements; Chromosomes; Chromosomes, Human, X - genetics; congenital cataract; Congenital diseases; Convulsions & seizures; Disruption; Female; Gene expression; Gene mapping; Genetic Diseases, X-Linked - etiology; Genetic Diseases, X-Linked - metabolism; Genetic Diseases, X-Linked - pathology; Genetic engineering; Genomes; Genotype & phenotype; Humans; Inversions; Male; Mapping; Membrane Proteins - genetics; Mutation; Nance-Horan syndrome; NHS; Patients; Pedigree; pericentric X inversion; structural variation (SV); Tooth Abnormalities - etiology; Tooth Abnormalities - metabolism; Tooth Abnormalities - pathology; Whole genome sequencing; whole-genome sequencing (WGS); topologically associated domains (TADs); structural variation (SV); NHS; Nance-Horan syndrome; whole-genome sequencing (WGS); chromosomal rearrangement; congenital cataract; position effects; pericentric X inversion
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222312713

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
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
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
expression in the proband and his unaffected mother, respectively. In conclusion, we report the first chromosomal inversion disrupting
, fine-mapped by WGS. Our data expand the clinical spectrum and the pathogenic mechanisms underlying the
defects.