期刊
CLINICAL GENETICS
卷 101, 期 1, 页码 127-133出版社
WILEY
DOI: 10.1111/cge.14071
关键词
exome sequencing; genome sequencing; kidney; phenotypic variability; renal failure; SHDRA; structural heart defects and renal anomalies syndrome; TMEM260; truncus arteriosus
资金
- Cancer Research UK
- European Union's Horizon 2020 [779257]
- Medical Research Council
- NHS England
- NIHR Oxford Biomedical Research Centre Programme
- Society for the Relief of Disabled Children, Hong Kong
- Wellcome Trust [203141/Z/16/Z]
This study confirms the genetic basis of SHDRA, expands its known mutational spectrum, and clarifies its clinical features. SHDRA is a severe condition associated with substantial mortality in early childhood, characterized by congenital cardiac malformations with a variable renal phenotype.
Only two families have been reported with biallelic TMEM260 variants segregating with structural heart defects and renal anomalies syndrome (SHDRA). With a combination of genome, exome sequencing and RNA studies, we identified eight individuals from five families with biallelic TMEM260 variants. Variants included one multi-exon deletion, four nonsense/frameshifts, two splicing changes and one missense change. Together with the published cases, analysis of clinical data revealed ventricular septal defects (12/12), mostly secondary to truncus arteriosus (10/12), elevated creatinine levels (6/12), horse-shoe kidneys (1/12) and renal cysts (1/12) in patients. Three pregnancies were terminated on detection of severe congenital anomalies. Six patients died between the ages of 6 weeks and 5 years. Using a range of stringencies, carrier frequency for SHDRA was estimated at 0.0007-0.007 across ancestries. In conclusion, this study confirms the genetic basis of SHDRA, expands its known mutational spectrum and clarifies its clinical features. We demonstrate that SHDRA is a severe condition associated with substantial mortality in early childhood and characterised by congenital cardiac malformations with a variable renal phenotype.
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