Relationship of genotype and clinical phenotype in a family with rare comorbidity of Marfan syndrome and hypochondroplasia caused by FBN1 and FGFR3 gene mutations
Objective To observe the clinical data of a family with rare comorbidity of Marfan syndrome and hypochondroplasia(HCH)caused by FBN1 and FGFR3 gene mutations,and to investigate the relationship between genotype and clinical phenotype.Methods A family with a rare comorbidity of Marfan syndrome and HCH caused by FBN1 and FGFR3 gene mutations was diagnosed and treated in Shanxi Provincial Children's Hospital on June 13,2021,and the clinical data were collected from the family members.The proband and his mother received whole exome sequence by high throughput sequencing method to identify the gene mutation sites.The mutation sites of the family members were verified by PCR-Sanger sequencing.A conservative analysis on mutation sites was done by Uniprot and Jalview software,and ACMG guideline was applied to evaluate their pathogenicity.Results The proband showed tall stature,funnel chest,and dislocation of lens while his mother and sister showed short stature,gonyectyposis,and dislocation of lens.Heterozygous missense mutation of c.364C＞T(p.Arg122Cys)in FBN1 gene in the proband caused the conversion of No.122 Arg to Cys in exon 5 of FBN1 gene EKG-like domain.Heterozygous missense mutations of c.364C＞T(p.Arg122Cys)in FBN1 gene and c.1620C＞G(p.Asn540Lys)in FGFR3 gene were found in the proband's mother and sister,in which FGFR3 gene mutation caused the conversion of No.540 Asp to Lys in exon 12 of FGFR3 gene TK1 domain.The c.364 site of FBN1 gene in four species(human,mouse,bovin,pig)and c.1620 site of FGFR3 gene in four species(human,chick,mouse,xenla)were highly conserved,and they were pathogenic and likely pathogenic respectively in the ACMG guideline rating.The FBN1 gene mutation led to Marfan syndrome in the proband,and FBN1 combined with FGFR3 gene mutations resulted in rare comorbidity of MFS and HCH in the proband's mother and sister.The proband and his wife received in vitro fertilization-embryo transfer in December 2021 and delivered a healthy boy in October 2022.Conclusion The tall stature of the proband is caused by FBN1 gene mutation,while the clinical manifestations in the skeletal system of the proband's mother and sister such as short stature are more correlated with FGFR3 gene mutation.
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