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Supplementary Material for: Genetic findings in short Turkish children born to consanguineous parents

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posted on 2024-06-05, 09:33 authored by Joustra S.D., Isik E., Wit J.M., Catli G., Anik A., Haliloglu B., Kandemir N., Ozsu E., Hendriks Y.M.C., deBruin C., Kant S.G., Campos-Barros A., Challis R.C., Parry D., Harley M.E., Jackson A., Losekoot M., vanDuyvenvoorde H.A.
Introduction The diagnostic yield of genetic analysis in the evaluation of children with short stature depends on associated clinical characteristics, but the additional effect of parental consanguinity has not been well documented. Methods This observational case series of 42 short children from 34 consanguineous families was collected by six referral centres of paediatric endocrinology (inclusion criteria: short stature and parental consanguinity). In eighteen patients (12 families, Group 1), the clinical features suggested a specific genetic defect in the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis, and a candidate gene approach was used. In others (Group 2) a hypothesis-free approach was chosen (gene panels, microarray analysis, and whole-exome sequencing), further subdivided into 11 patients with severe short stature (height <-3.5 SDS) and microcephaly (head circumference <-3.0 SDS) (group 2a), 10 patients with syndromic short stature (group 2b) and were 3 patients with nonspecific isolated GH deficiency (group 2c). Results In all 12 families from group 1, (likely) pathogenic variants were identified in GHR, IGFALS, GH1, and STAT5B. In 9/12 families from group 2a, variants were detected in PCNT, SMARCAL1, SRCAP, WDR4 and GHSR. In 5/9 families from group 2b, variants were found in TTC37, SCUBE3, NSD2, RABGAP1, and 17p13.3 microdeletions. In group 2c no genetic cause was found. Homozygous, compound heterozygous and heterozygous variants were found in 21, 1 and 4 patients, respectively. Conclusion Genetic testing in short children from consanguineous parents has a high diagnostic yield, especially in cases of severe GH deficiency or insensitivity, microcephaly, and syndromic short stature.

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