Novel genotypes and phenotypes among Chinese patients with Floating-Harbor syndrome

Abstract

Background: Floating-Harbor syndrome (FHS) is a rare syndromic short stature disorder caused by truncating variants in SRCAP. Few Chinese FHS patients had been reported so far and limited knowledge regarding the benefit of growth hormone treatment existed.

Methods: We ascertained 12 short stature patients with molecularly confirmed diagnosis of FHS by whole exome sequencing. We performed a comprehensive clinical evaluation for all patients and assessed the responsiveness of growth hormone treatment in a subset of the patients.

Results: Five distinct pathogenic/likely pathogenic variants were identified in 12 independent FHS patients including two previously reported variants (c.7303C > T/p.Arg2435Ter and c.7330C > T/p.Arg2444Ter) and three novel variants (c.7189G > T/p.Glu2397Ter, c.7245_7246delAT/p.Ser2416ArgfsTer26 and c.7466C > G/p.Ser2489Ter). The c.7303C > T/p.Arg2435Ter mutation appears more common in Chinese FHS patients. The clinical presentations of Chinese FHS patients are very similar to those of previously reported patients of different ethnicities. Yet we noticed micropenis and ear abnormalities in multiple patients, suggesting that these may be novel phenotypes of Floating-Harbor syndrome. Eight patients (one with GH deficiency, one with undetermined GH level, six without GH deficiency) underwent growth hormone treatment, 3 patients had good responses, one with modest and two with poor responses.

Conclusion: We described novel genotypes and phenotypes in a Chinese FHS patient cohort. We showed that about half of FHS patients exhibited modest to good response to GH treatment regardless of their respective GH deficiency status. We didn't find any correlation between different mutations and response to GH treatment.

Keywords: Chinese; Floating-Harbor syndrome; Growth hormone deficiency; SRCAP; Short stature.

Fig. 1

Facial features of nine Chinese patients with FHS. Noticeable features included triangular face, long eyelashes, large and low-set ears, ear deformities, prominent nose, large nares, low-hanging columella, short philtrum, thin vermilion border of the upper lip and small teeth and/or widely spaced teeth

Fig. 2

Hands and feet of seven Chinese patients with FHS. These photos showing brachydactyly, broad toes and thumbs, clubbing fingers, broad fingertips, the fourth and fifth fingers clinodactyly and small toenails

Fig. 3

The wrist X-ray results of nine patients with FHS. These photos indicating the bone age delay in each patient. The chronological ages and corresponding bone ages are listed in Table 1

Fig. 4

The Summary of reported mutations and novel mutations in FHS patients. Green dots represent mutations found in our cohort; Purple dots represent mutations previously reported in literature. Each point represent one case. The number in circle represent the times of mutations reported. The mutations marked with red color are novel mutations. Three deep blue bars represent three C-terminal AT-hook motifs. The coordinates refer to SRCAP cDNA sequence positions