Whole exome sequencing confirms the clinical diagnosis of Marfan syndrome combined with X-linked hypophosphatemia

Abstract

BackgroundTo determine the genetic lesions and to modify the clinical diagnosis for a Chinese family with significant intrafamilial phenotypic diversities and unusual presentations.MethodsThree affected patients and the asymptomatic father were included and received comprehensive systemic examinations. Whole exome sequencing (WES) was performed for mutation detection. Structural modeling test was applied to analyze the potential structural changes caused by the missense substitution.ResultsThe proband showed a wide spectrum of systemic anomalies, including bilateral ectopia lentis, atrial septal defect, ventricular septal defect, widening of tibial metaphysis with medial bowing, and dolichostenomelia in digits, while her mother and elder brother only demonstrated similar skeletal changes. A recurrent mutation, PHEX p.R291*, was found in all patients, while a de novo mutation, FBN1 p.C792F, was only detected in the proband. The FBN1 substitution was also predicted to cause significant conformational change in fibrillin-1 protein, thus changing its physical and biological properties.ConclusionsTaken together, we finalized the diagnosis for this family as X-linked hypophosphatemia (XLH), and diagnosed this girl as Marfan syndrome combined with XLH, and congenital heart disease. Our study also emphasizes the importance of WES in assisting the clinical diagnosis for complicated cases when the original diagnoses are challenged.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0534-9) contains supplementary material, which is available to authorized users.

Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees

“…To reveal the disease causing mutation in the two families, we selectively performed whole exome sequencing (WES) on three participants in family A (A-IV:3, A-VI:2 and A-VI:3) and two patients in family B (B-III:4 and B-IV:1). WES was conducted with the 44.1 megabases SeqCap EZ Human Exome Library v2.0 (Roche NimbleGen, Madison, WI) for enrichment of 23588 genes on patients from family A [ 6 ], and with SureSelect Human All Exon V6 60 Mb Kit (Agilent Technologies, Santa Clara, CA) on patients from family B [ 7 ]. Briefly, qualified genomic DNA samples were randomly sheared by Covaris into 200–250 base pair (bp) fragments.…”