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Multigene Sequencing Analysis of Children Born Small for Gestational Age With Isolated Short Stature.

CONTEXT
Patients born small for gestational age (SGA) who present with persistent short stature could have an underlying genetic etiology that will account for prenatal and postnatal growth impairment. We applied a unique massive parallel sequencing approach in cohort of patients with exclusively nonsyndromic SGA to simultaneously interrogate for clinically substantial genetic variants.


OBJECTIVE
To perform a genetic investigation of children with isolated short stature born SGA.


DESIGN
Screening by exome (n = 16) or targeted gene panel (n = 39) sequencing.


SETTING
Tertiary referral center for growth disorders.


PATIENTS AND METHODS
We selected 55 patients born SGA with persistent short stature without an identified cause of short stature.


MAIN OUTCOME MEASURES
Frequency of pathogenic findings.


RESULTS
We identified heterozygous pathogenic or likely pathogenic genetic variants in 8 of 55 patients, all in genes already associated with growth disorders. Four of the genes are associated with growth plate development, IHH (n = 2), NPR2 (n = 2), SHOX (n = 1), and ACAN (n = 1), and two are involved in the RAS/MAPK pathway, PTPN11 (n = 1) and NF1 (n = 1). None of these patients had clinical findings that allowed for a clinical diagnosis. Seven patients were SGA only for length and one was SGA for both length and weight.


CONCLUSION
These genomic approaches identified pathogenic or likely pathogenic genetic variants in 8 of 55 patients (15%). Six of the eight patients carried variants in genes associated with growth plate development, indicating that mild forms of skeletal dysplasia could be a cause of growth disorders in this group of patients.