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. 2020 Oct 14;15(1):288.
doi: 10.1186/s13023-020-01572-9.

Phenotypic and genetic spectrum of isolated macrodactyly: somatic mosaicism of PIK3CA and AKT1 oncogenic variants

Wen Tian  1 , Yingzhao Huang  2   3   4 , Liying Sun  1 , Yang Guo  1 , Sen Zhao  2   3   4 , Mao Lin  2   3   4 , Xiying Dong  2   3   4 , Wenyao Zhong  1 , Yuehan Yin  1 , Zefu Chen  2   3   4 , Nan Zhang  1 , Yuanqiang Zhang  2   3   4 , Lianlei Wang  2   3   4 , Jiachen Lin  2   3   4 , Zihui Yan  2   3   4 , Xinzhuang Yang  5 , Junhui Zhao  1 , Guixing Qiu  2   3   4 , Jianguo Zhang  2   3   4 , Zhihong Wu  6   7   8 , Nan Wu  9   10   11 ; (Deciphering Disorders Involving Scoliosis, COmorbidities) study group
Affiliations

Phenotypic and genetic spectrum of isolated macrodactyly: somatic mosaicism of PIK3CA and AKT1 oncogenic variants

Wen Tian et al. Orphanet J Rare Dis. .

Abstract

Background: Isolated macrodactyly is a severe congenital hand anomaly with functional and physiological impact. Known causative genes include PIK3CA, AKT1 and PTEN. The aim of this study is to gain insights into the genetics basis of isolated macrodactyly.

Results: We enrolled 24 patients with isolated macrodactyly. Four of them were diagnosed with Proteus syndrome based on skin presentations characteristic to this disease. Targeted next-generation sequencing was performed using patients' blood and affected tissues. Overall, 20 patients carry mosaic PIK3CA pathogenic variants, i.e. p.His1047Arg (N = 7), p.Glu542Lys (N = 6), p.Glu545Lys (N = 2), p.His1047Leu (N = 2), p.Glu453Lys (N = 1), p.Gln546Lys (N = 1) and p.His1047Tyr (N = 1). Four patients who met the diagnostic criteria of Proteus syndrome carry mosaic AKT1 p.Glu17Lys variant. Variant allele frequencies of these mosaic variants obtained through next-generation sequencing range from 10 to 33%. In genotype-phenotype correlation analysis of patients with PIK3CA variant, we found that patients with the macrodactyly of the lower limbs tend to carry PIK3CA variants located in the helical domain (P = 0.005).

Conclusions: Mosaic PIK3CA and AKT1 variants can be found in all of our samples with isolated macrodactyly. Insights into phenotypic and genetic spectrum of isolated macrodactyly may be helpful in perusing a more precise and effective management of isolated macrodactyly.

Keywords: AKT1 serine/threonine kinase 1 (AKT1); Macrodactyly; Phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA); Proteus syndrome; Somatic mosaicism.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Representative clinical photographs of nine macrodactyly patients. a Patient No. 1. b Patient No. 2. c Patient No. 3. d Patient No. 18. e Patient No. 6. f Patient No. 15. g Patient No. 19. h Patient No. 16. i Patient No. 21
Fig. 2
Fig. 2
Distribution of PIK3CA variants identified in this study by functional domains. ABD: PI3K-ABD domain. RBD: PI3K-RBD domain. C2: C2 PI3K-type domain. Helical: PIK helical domain. Kinase: PI3K/PI4K kinase domain. A dot represents a PIK3CA variant identified in one patient
See this image and copyright information in PMC

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