AUTHOR=Shangguan Huakun , Chen Ruimin 

TITLE=Phenotypes of Cornelia de Lange syndrome caused by non-cohesion genes: Novel variants and literature review

JOURNAL=Frontiers in Pediatrics

VOLUME=10

YEAR=2022

URL=https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2022.940294

DOI=10.3389/fped.2022.940294

ISSN=2296-2360

ABSTRACT=<sec><title>Background</title><p>Cornelia de Lange syndrome (CdLS) is a genetic disorder caused by variants in cohesion genes including <italic>NIPBL</italic>, <italic>SMC1A</italic>, <italic>SMC3</italic>, <italic>RAD21</italic>, and <italic>HDAC8.</italic> According to the 2018 consensus statement, a patient with clinical scored ≥ 11 points could be diagnosed as CdLS. However, some variants in non-cohesion genes rather than cohesion genes can manifest as phenotypes of CdLS.</p></sec><sec><title>Objectives</title><p>This study describes six variants of non-cohesion genes (<italic>KDM6A</italic>, <italic>KMT2D, KMT2A ANKRD11</italic>, and <italic>UBE2A</italic>), and assesses the reliability of 11-points scale criteria in the clinical diagnosis of CdLS.</p></sec><sec><title>Methods</title><p>Whole-exome sequencing (WES) was performed on six patients with features of CdLS. Phenotypic and genotypic spectra of 40 previously reported patients with features of CdLS caused by non-cohesion genes variants and 34 previously reported patients with <italic>NIPBL</italic> variants were summarized. Clinical score comparison among patients with <italic>NIPBL</italic> variants versus those with variants in non-cohesin genes was performed.</p></sec><sec><title>Results</title><p>Variants in non-cohesion genes were found in six patients [<italic>KMT2A</italic> (<italic>n</italic> = 2), <italic>KMT2D</italic>, <italic>ANKRD11</italic>, <italic>KDM6A</italic>, and <italic>UBE2A</italic>]. Of them, four variants (<italic>KMT2A</italic> c.7789C &gt; T, <italic>ANKRD11</italic> c.1757_1776del, <italic>KDM6A</italic> c.655-1G &gt; A, and <italic>UBE2A</italic> c.439C &gt; T) were novel. Combining with previously reported cases, 46 patients with phenotypes of CdLS caused by variants in 20 non-cohesion genes are now reported. From this total cohort, the average clinical score of patients in <italic>ANKRD11</italic> cohort, <italic>SETD5</italic> cohort, and <italic>AFF4</italic> cohort was statistically lower than those in <italic>NIPBL</italic> cohort (8.92 ± 1.77 vs. 12.23 ± 2.58, 7.33 ± 2.52 vs. 12.23 ± 2.58, 5.33 ± 1.53 vs. 12.23 ± 2.58; <italic>p</italic> &lt; 0.05). The average clinical score of <italic>KMT2A</italic> cohort, <italic>EP300</italic> cohort, and <italic>NIPBL</italic> cohort had not significantly different from (11 ± 2.19 vs. 12.23 ± 2.58, 10 ± 4.58 vs. 12.23 ± 2.58; <italic>p</italic> &gt; 0.05).</p></sec><sec><title>Conclusion</title><p>We described 4 novel variants of non-cohesion genes in six Chinese patients with phenotypes of CdLS. Of note, three genes (<italic>KMT2D</italic>, <italic>KDM6A</italic>, and <italic>UBE2A</italic>) causing features of CdLS have never been reported. The proposed clinical criteria for CdLS needed to be updated and refined, insofar as WES was necessary to confirm the diagnosis of CdLS. Our study expanded the spectra of non-cohesion genetic variations in patients with features of CdLS.</p></sec>