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.

Objective: To assess the results of the first trimester combined test to design a prenatal protocol for the introduction of the cell-free fetal DNA test as a contingent screening model. Method: An observational retrospective study in 12,327 singleton pregnancies to analyze the results of the combined first trimester screening, the nuchal translucency ≥97.5 percentile, their cytogenetic results and birth outcomes. Results: A total of 533 (4.3%) pregnant women had a risk in combined first trimester screening above 1/300. In this group, sixty nine had an unbalanced karyotype. The abnormal/normal karyotype ratio was 1/28 in pregnant women with intermediate risk (1/51-1/300) for trisomy 21 and trisomy 18, 1/58 with intermediate risk just for trisomy 21 and 1/37 with intermediate risk just for trisomy 18. A 19.8% of the unbalanced karyotypes had chromosomal abnormalities other than trisomies 21, 18 and 13. Two false negatives cases at first trimester combined screening presented a nuchal translucency ≥ p97.5^th. Conclusion: We propose the introduction of the cell-free fetal DNA test when the risk of first trimester combined screening is intermediate (1/51–1/300) and when nuchal translucency is ≥ p97.5^th with a low risk in the combined screening. This policy would allow us to continue to detect uncommon chromosomal abnormalities.