ESPE2023 Rapid Free Communications Growth and syndromes (to include Turner syndrome) (6 abstracts)
Genetic findings in short Turkish children born to consanguineous parents
Sjoerd Joustra 1 , Emregul Isik 2 , Jan M. Wit 1 , Gonul Catli 3 , Ahmet Anik 4 , Belma Haliloglu 5 , Nurgun Kandemir 6 , Elif Ozsu 7 , Yvonne Hendriks 1 , Christiaan de Bruin 1 , Sarina Kant 8 , Angel Campos-Barros 9 , Rachel Challis 10 , David Parry 10 , Margaret Harley 10 , Andrew Jackson 10 , Monique Losekoot 1 & Hermine van Duyvenvoorde 1
1Leiden University Medical Center, Leiden, Netherlands. 2Ankara Bilkent City Hospital, Ankara, Turkey. 3Izmir Katip Celebi University Faculty of Medicine, Izmir, Turkey. 4Dokuz Eylul University, Izmir, Turkey. 5Marmara University School of Medicine, Istanbul, Turkey. 6Hacettepe University, Ankara, Turkey. 7University of Ankara, Ankara, Turkey. 8Erasmus Medical Center, Rotterdam, Netherlands. 9Hospital Universitario La Paz, Madrid, Spain. 10University of Edinburgh, Edinburgh, United Kingdom
Objective: To describe clinical, laboratory and genetic characteristics of 42 short children from 34 consanguineous Turkish families.
Design: Descriptive case series.
Methods: After collecting clinical information, DNA samples were analysed in three European laboratories. In 18 children (12 families) suspected of a genetic defect in the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis (Group 1), a candidate gene approach was performed. In groups 2 (severe microcephalic short stature), 3 (syndromic short stature) and 4 (GH deficiency) an hypothesis-free approach was used (microarray analysis, NGS-based targeted gene panels and whole exome sequencing).
Results: In Group 1, genetic defects were identified in all 12 families: GH1 (n=1), GHR (n=5), STAT5B (n=1) and IGFALS (n=5). In group 2, genetic defects were detected in 9 out of 10 families. Homozygous PCNT mutations (3 novel) were found in five children with MOPD2 from four families. An identical homozygous SMARCAL1 mutation was found in two children from two families who were not aware of any family connection (but live in the same city) (Schimke immune-osseous dysplasia). One child was homozygous for a novel WDR4 mutation, consistent with a recently described type of primordial dwarfism. One patient carried a heterozygous de novo variant in SRCAP (Floating Harbor syndrome) and another was heterozygous for a maternal GHSR variant. In nine families in group 3 (syndromic short stature), five genetic defects were identified. One child carried two 17p13.3 microdeletions, containing YWHAE and CRK but not PAFAH1B1. One child was homozygous for a TTC37 variant (Trichohepatoenteric syndrome 1); two siblings were homozygous for a novel SCUBE3 mutation; one child was homozygous for a novel RABGAP1 mutation; and one patient had a novel de novo heterozygous NSD2 variant (Rauch-Steindl syndrome). In three children with partial GH deficiency no genetic cause was found. Most genetic defects were homozygous (21/26), one was compound heterozygous and four were heterozygous. Thirteen variants were novel.
Conclusions: For children with consanguineous parents presenting with severe GH deficiency or insensitivity, a candidate approach was successful in all cases. In those with severe microcephalic short stature and other forms of syndromic short stature, the diagnostic yield was 90% and 56%, respectively. In contrast, no genetic cause could be detected in children with partial GH deficiency. In short children suspected for an abnormality of the GH-IGF-I axis or non-isolated short stature, with a family history of consanguinity, genetic testing leads to a high diagnostic yield.
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