medwireNews: Rare copy number variants (CNVs) have been identified in a study of children who have growth hormone insensitivity (GHI) or insulin-like growth factor-1 (IGF-1) insensitivity, shedding light on the  genetic basis of their conditions.

“The identification of a pathogenic molecular defect is important for patients, families and clinicians as it avoids unnecessary investigations and/or treatment, ends uncertainty and allows appropriate genetic counselling”, explain Helen Storr, from Barts and the London School of Medicine, Queen Mary University of London in the UK, and co-workers.

“It is also fundamental to identify co-morbidities associated with syndromic [short stature]”, they write in the European Journal of Endocrinology.

The team investigated the role of CNVs – chromosomal imbalances caused by deletions or duplications that affect one or more genes or a chromosomal region – among 53 patients with GHI, aged an average of 7.4 years, who had short stature (mean height standard deviation score [SDS] of –3.9), normal–high levels of GH and IGF-1 deficiency (average SDS –2.5).

Ten patients with IGF-1 insensitivity, aged an average of 5.8 years, were also assessed, all of whom had short stature (mean height SDS –3.4) and normal–high levels of GH and IGF-1.

Genomic DNA analysis identified pathogenic or likely pathogenic CNVs in seven (11%) patients and a CNV of uncertain significance in three (5%) patients. Patients with and without a CNV did not differ significantly with regard to height, age, sex, bodyweight or IGF-1 SDS, the researchers note.

These pathogenic or likely pathogenic CNVs were detected in six of the seven affected GHI patients and one of three IGF-1 insensitivity patients.

The investigators note that five of the GHI patients with CNVs had clinical features of Silver–Russell Syndrome (SRS), defined by a Netchine-Harbison clinical scoring system (NH-CSS) score of 2 or more, as well as SRS-like features; one patient fulfilled the SRS diagnostic criteria of a 3/6 NH-CSS score plus a recognised genetic cause of 1q21 deletion.

Indeed, six of the seven GHI patients with CNVs had SRS features or associated SRS features when disregarding postnatal growth failure as a feature, compared with just eight of the 46 GHI patients without CNVs, a statistically significant difference.

The team notes that 38% of the 13 CNVs identified in the study had previously been reported in patients with SRS-like features.

The CNV regions of the GHI and IGF-1 insensitivity patients were calculated to contain 122 and 26 different protein-coding genes, respectively. The WNT canonical pathway was enriched in two of the GHI patients and another three GHI patients had weak evidence for enrichment of this pathway, while analysis suggested that CLOCK was a “plausible common upstream regulator” affected by CNVs in two IGF-1 insensitivity patients.

“This is particularly interesting as IGF-1 regulates clock gene expression”, the researchers write, noting that CLOCK helps modulate cellular hypothalamic circadian rhythms and cell cycle progression.

Overall, 45 candidate growth genes were identified within the CNV regions of nine patients. This included 15 genes in five patients that have previously been associated with height in genome-wide association studies, while one patient had a 12q14 deletion in HMGA2, a gene previously linked to growth failure.

“The limitation is that only protein-coding candidate genes are identified by this approach and not imprinting control regions which may impact growth, e.g. chromosome 7 alterations”, the researchers admit.

Nevertheless, the team identified multiple direct and indirect protein–protein interactions between genes present in the CNV regions of both the GHI and IGF-1 insensitivity cohort, including genes involved in the cell cycle process.

“Overrepresentation of cyclin dependent protein kinases in CNV loci [suggests] an association between the genes and short stature”, the researchers postulate.

The team concludes that “[r]are CNVs were a relatively common cause of milder non-classical phenotypes in our cohort.”

“This expands the known phenotypes of rare CNVs, potentially identifies new candidate [short stature] genes and expands the spectrum of GHI/IGF-1 insensitivity and overlapping disorders such as SRS”, they continue.

Storr et al recommend: “CNV analysis should be carried out in all short patients where no monogenic cause has been identified, particularly those with features of GHI, IGF-1 insensitivity and concomitant subtle features of SRS.

“Functional experimental evidence is now required to validate the candidate growth genes, interactions and biological pathways enriched in our cohort.”

By Lynda Williams

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Eur J Endocrinol 2020; doi:10.1530/EJE-20-0474