IMPE Abstracts

Introduction: Short stature is a common phenotype among patients with congenital syndromic disorders. However, the clinical diagnosis of such patients is often difficult because of their rarity and phenotypic complexity.

Objective: To investigate the genetic etiology of syndromic short stature of unknown cause in our institute.

Methods: We performed trio whole-exome sequencing in 35 unrelated Japanese patients with syndromic short stature of unknown cause and their parents. Syndromic short stature is defined as a height below -2 standard deviation score with additional manifestations such as dysmorphic features, skeletal dysplasia, developmental delay, and intellectual disability.

Results: We identified heterozygous pathogenic variants in known causative genes for syndromic short stature in twelve patients (34%). Two sporadic patients were diagnosed as Noonan syndrome (c.739T>C, p.Phe247Leu in BRAF; c.1234C>T, p.Arg412Cys in LZTR1). Two different ACAN mutations were identified in two independent familial cases of brachydactyly and mild dysmorphic facial features (c.1744delT, p.Phe582fs and c.7111dupT, p.Asn2370fs). Other eight sporadic patients were diagnosed as CHARGE syndrome (c.4480C>T, p.Arg1494* in CHD7), Wiedemann-Steiner syndrome (c.6761delC, p.Thr2254fs in KMT2A), mandibulofacial dysostosis (c.1567dupC, p.Gln523fs in EFTUD2), Okur-Chung neurodevelopmental syndrome (c.593A>G, p.Lys198Arg in CSNK2A1), Culler-Jones syndrome (c.3369delG, p.Met1123fs in GLI2), Coffin-Siris syndrome (c.1035_1053del, p.Ala345fs. in ARID1B), Genitopatellar syndrome (c.3362delT, p.Ile1121fs in KAT6B), and, Bryant-Li-Bhoj Neurodevelopmental Syndrome 1（c.79C>T, p.Arg27Cys in H3-3A）, respectively. No candidate genes have been identified in other patients.

Conclusions: Although trio whole-exome sequencing is a powerful tool for diagnosis of rare growth disorders, the causes of syndromic short stature still remain elusive in more than a half of patients. Accumulation and more comprehensive genetic analysis of patients with similar phenotypes are required to clarify the molecular pathogenesis of syndromic short stature.