Background: The majority of children with short stature are classified as idiopathic short stature. Whole exome sequencing can help identify genetic causes of short stature.
Methods: We recruited 10 children with 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 nonsynonymous genetic variants that might cause the short stature. All rare allelic variants were confirmed by Sanger and were absent in 609 exomas of Brazilian healthy subjects and in a public database (EXAC).
Results: We identified two novel candidate genes with loss of function (LoF) mutations. One patient has a homozygous nonsense allelic variant in RAB3IP (c.13A> T: p.K5*). The RAB3IP is an important factor for activation of specific proteins in the RAS family, known as RAB8A/B. These proteins participate in the ciliary and exocytosis process. This latter feature may be involved in hormone secretion. This patient has short stature with microcephaly, mild dysmorphic facial, mild disorder of sex development and a suggestive resistance hormonal profile with an important elevation of LH and FSH. The second patient has a de novo heterozygous variant in DGCR8 gene (c.1321C>T/p.R441*). No phenotype was associated with DGCR8 alteration in humans. This gene participates in microRNA biogenesis and it is extremely intolerant for LoF alterations. It was mapped in the chromosome 22q11.2 in a critical region of DiGeorge syndrome, which is associated with growth impairment. This patient was small for gestational age without catch-up growth and had a neonatal hypomagnesemia, mild delay in initial development and mild dysmorphic facial features.
Conclusion: It is possible that RAB3IP and DGCR8 genes have a relationship with a dysmorphic features and short stature in these patients. The identification of other patient with similar phenotype and genetic findings is important to prove this relationship.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology