Whole Exome Sequencing to Identify Genetic Causes of Short Stature

Abstract

Background/Aims: Short stature is a common reason for presentation to pediatric endocrinology clinics. However, for most patients, no cause for the short stature can be identified. As genetics plays a strong role in height, we sought to identify known and novel genetic causes of short stature. Methods: We recruited 14 children with severe short stature of unknown etiology. We conducted whole exome sequencing of the patients and their family members. We used an analysis pipeline to identify rare non-synonymous genetic variants that cause the short stature. Results: We identified a genetic cause of short stature in 5 of the 14 patients. This included cases of floating-harbor syndrome, Kenny-Caffey syndrome, the progeroid form of Ehlers-Danlos syndrome, as well as 2 cases of the 3-M syndrome. For the remaining patients, we have generated lists of candidate variants. Conclusions: Whole exome sequencing can help identify genetic causes of short stature in the context of defined genetic syndromes, but may be less effective in identifying novel genetic causes of short stature in individual families. Utilized in the clinic, whole exome sequencing can provide clinically relevant diagnoses for these patients. Rare syndromic causes of short stature may be underrecognized and underdiagnosed in pediatric endocrinology clinics.

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

“…In the first decade of the 21st century, the genetic toolbox was expanded by whole genome single nucleotide polymorphism (SNP) array (1) and array-comparative genomic hybridization (array-CGH) (2) for the detection of microdeletions or microduplications (copy number variants (CNVs)), the former of which is also able to detect uniparental disomy. In the second decade an even more successful tool became available -whole exome sequencing (WES) -for the detection of gene variants as possible causes of congenital disorders (3,4,5,6), with a good diagnostic yield in well-selected patients (6). In general, WES is performed in an index patient and his/her parents (a 'trio'), and (if available) affected and non-affected siblings, to limit the number of informative variants in the bioinformatic analysis.…”

IGF-I Deficiency in the Era of Genomics: Lessons Learned

“…However, there is some evidence to suggest that exome sequencing will identify a monogenic cause in patients with more severe short stature or those with syn- dromic features. Our group, for example, previously found a genetic etiology in 5 out of 14 patients with severe syndromic short stature who underwent exome sequencing [2]. The current study focused on patients with severe primary IGF-I deficiency, a subgroup of growth disorders which one would posit to have a higher likelihood of monogenic causes, especially since human mutations have been found in multiple genes in the growth hormone/IGF-I axis [3].…”

Whole Exome Sequencing in Short Stature: Finding Needles in the Haystack

“…The price of WES is dropping, and our ability to rapidly filter the background ‘noise' of inconsequential genetic variants is improving. With additional studies of WES in larger groups, some of the ‘maybes' found by Guo et al [1] in this population will become definitive diagnoses and WES will become routine in the evaluation of short stature.…”

“…In this issue, Guo et al [1] describe the results of whole exome sequencing (WES) in 14 patients like the one described above. They sought rare, highly penetrant, monogenic variants as potential explanations for each patient's condition.…”

“…Not only were specific diagnoses reached in a high proportion of the patients, the results also provided new insight into specific genetic conditions. Guo et al [1] diagnosed Kenny-Caffey and Ehlers-Danlos syndromes by WES in 2 patients who indeed demonstrated a few features of their respective syndromes, but evidently insufficient to provoke examination of the specific genes. This shows us once again that when genetic testing is applied early in the evaluation of patients, we uncover less complete forms of disease.…”