Genetic findings in short Turkish children born to consanguineous parents

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.