An investigation of the etiology and follow‐up findings in 35 children with overgrowth syndromes, including biallelic SUZ12 variant

Abstract

Overgrowth-intellectual disability (OGID) syndromes are clinically and genetically heterogeneous group of disorders. The aim of this study was to examine the molecular etiology and long-term follow-up findings of Turkish OGID cohort. Thirty-five children with OGID were included in the study. Single gene sequencing, clinical exome analysis, chromosomal microarray analysis and whole exome sequencing were performed. Five pathogenic copy number variants were detected in the patients; three of them located on chromosome 5q35.2 (encompassing NSD1), others on 9q22.3 and 22q13.31. In 19 of 35 patients; we identified pathogenic variants in OGID genes associated with epigenetic regulation, NSD1 (n = 15), HIST1H1E (n = 1), SETD1B(n = 1), and SUZ12 (n = 2). The pathogenic variants in PIK3CA (n = 2), ABCC9 (n = 1), GPC4 (n = 2), FIBP (n = 1), and TMEM94 (n = 1) which had a role in other growth pathways were detected in seven patients. The diagnostic yield was 31/35(88%).Twelve pathogenic variants were novel. The common facial feature of the patients was prominent forehead. The patients with Sotos syndrome were observed to have milder intellectual disability than patients with other OGID syndromes. In conclusion, this study showed, for the first time, that biallelic variants of SUZ12 caused Imagawa-Matsumoto syndrome, monoallelic variants in SETDIB resulted in OGID. Besides expanded the phenotypes of very rare OGID syndromes caused by FIBP and TMEM94.

Letter to the Editor regarding “New cases of recently described Thauvin‐Robinet‐Faivre syndrome with a novel homozygous FIBP gene variant” by Kılıç and Koşukçu, “An investigation of the etiology and follow‐up findings in 35 children with overgrowth syndromes, including biallelic SUZ12 variant” by Yüksel Ülker et al. and “Expanding the phenotype and genotype in Thauvin‐Robinet‐Faivre syndrome: A new patient with a novel variant and additional clinica

“…We read with pleasure the recent AJMG Part A publication "New cases of recently described Thauvin-Robinet-Faivre syndrome with a novel homozygous FIBP gene variant" (Kilic & Kosukcu, 2023) that present two new patients with overgrowth, intellectual disability, dysmorphic features and homozygous c.412-3_415dup-CAGTTTG (p. Asp139AlafsTer3) variant in the FIBP gene (NM_004214.5). This variant has been reported as novel in three different publications (including ours) that were published in close succession (Duzenli et al, 2023;Yuksel Ulker et al, 2023). The authors of these three papers have assumed that their paper was the third after the papers by Thauvin-Robinet et al and Akawi et al and this situation may cause confusion for future literature reviews (Akawi et al, 2016;Thauvin-Robinet et al, 2016).…”