Abstract
BackgroundFollistatin‐like 1 (Fstl1) is a glycoprotein expressed throughout embryonic development. Homozygous loss of Fstl1 in mice results in skeletal and respiratory defects, leading to neonatal death due to a collapse of the trachea. Furthermore, Fstl1 conditional deletion from the endocardial/endothelial lineage results in postnatal death due to heart failure and profound atrioventricular valve defects. Here, we investigated patients with phenotypes similar to the phenotypes observed in the transgenic mice, for variants in FSTL1.MethodsIn total, 69 genetically unresolved patients were selected with the following phenotypes: campomelic dysplasia (12), small patella syndrome (2), BILU (1), and congenital heart disease patients (54), of which 16 also had kyphoscoliosis, and 38 had valve abnormalities as their main diagnosis. Using qPCR, none of 69 patients showed copy number variations in FSTL1. The entire gene body, including microRNA‐198 and three validated microRNA‐binding sites, were analyzed using Sanger sequencing.ResultsNo variants were found in the coding region. However, 8 intronic variants were identified that differed significantly in their minor allele frequency compared to controls. Variant rs2272515 was found to significantly correlate (p < 0.05) with kyphoscoliosis.ConclusionWe conclude that pathogenic variants in FSTL1 are unlikely to be responsible for skeletal or atrioventricular valve anomalies in humans.
Highlights
3%–4% of all life‐born babies have a congenital malformation
The finding that Follistatin‐like 1 (Fstl1) KO mice display both abnormal spine curvature and respiratory distress at birth can point toward kyphoscoliosis, a musculoskeletal disorder characterized by an abnormal curve of the spine that causes extrapulmonary restriction of the lungs that further results in impairment of pulmonary functions (Pajdzinski et al, 2017)
The second novel variant is positioned at chr3:120,121,556 and is a G > T nucleotide change located in intron 9, in a patient with campomelic dysplasia
Summary
3%–4% of all life‐born babies have a congenital malformation. In a minority of these cases, the underlying cause is identified as a chromosomal abnormality, a familial or de novo pathogenic variations, or as an environmental cause (e.g., pollution, alcohol abuse), or a combination of these conditions (Kuciene & Dulskiene, 2008; Liu et al, 2009). The finding that Fstl KO mice display both abnormal spine curvature and respiratory distress at birth can point toward kyphoscoliosis, a musculoskeletal disorder characterized by an abnormal curve of the spine that causes extrapulmonary restriction of the lungs that further results in impairment of pulmonary functions (Pajdzinski et al, 2017) These patients often have psychological problems (for example, anxiety, difficulty in performing daily activities) which are observed in mice, in which Fstl is genetic deleted from the small dorsal root ganglion neurons (Li et al, 2011). This study aimed at identifying whether variations in FSTL1 underlie human congenital abnormalities that show phenotypic similarity with those that are observed in the Fstl KO and/or Fstl endoKO mice To this end, we selected 69 patients with genetically unresolved campomelic dysplasia, small patella syndrome, BILU syndrome, kyphoscoliosis and/or defects of the mitral or tricuspid valves, and Sanger sequenced the FSTL1 gene body and determined the copy number
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