Phenotypic and genetic spectrum of isolated macrodactyly: somatic mosaicism of PIK3CA and AKT1 oncogenic variants
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RESEARCH
Phenotypic and genetic spectrum of isolated macrodactyly: somatic mosaicism of PIK3CA and AKT1 oncogenic variants Wen Tian1†, Yingzhao Huang2,3,4†, Liying Sun1, Yang Guo1, Sen Zhao2,3,4, Mao Lin2,3,4, Xiying Dong2,3,4, Wenyao Zhong1, Yuehan Yin1, Zefu Chen2,3,4, Nan Zhang1, Yuanqiang Zhang2,3,4, Lianlei Wang2,3,4, Jiachen Lin2,3,4, Zihui Yan2,3,4, Xinzhuang Yang5, Junhui Zhao1, Guixing Qiu2,3,4, Jianguo Zhang2,3,4, Zhihong Wu3,4,5* and Nan Wu2,3,4* on behalf of (Deciphering Disorders Involving Scoliosis, COmorbidities) study group
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: Macrodactyly, Phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA), AKT1 serine/threonine kinase 1 (AKT1), Somatic mosaicism, Proteus syndrome
*Correspondence: [email protected]; [email protected] † Wen Tian and Yingzhao Huang contributed equally to this work 2 Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing 100730, China 5 Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing 100730, China Full list of author information is available at the end of the article
Introduction Macrodactyly is a rare congenital anomaly characterized by the overgrowth of digits on one or multiple limbs, which can present as either isolated or syndromic (in conjunction with other congenital defects) macrodactyly. It occurs in approximately 1/50,000–1/100,000 live births, and varies according to regional
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