Exome sequencing identifies a novel homozygous variant in NDRG4 in a family with infantile myofibromatosis

Abstract

Infantile myofibromatosis (IM) is a rare disorder characterized by the development of benign tumors in the skin, muscle, bone, and viscera. The incidence is 1/150,000 live births and the disease is the most common cause of fibrous tumors in infancy. Cases which lack visceral involvement generally have a more benign course, usually with spontaneous regression of the tumors. On the other hand, the prognosis tends to be unfavorable when there is involvement of vital organs, which can lead to significant mortality. The identification of rare variants in genes that may cause IM is the first step towards the possibility of targeted treatments; however, the molecular pathogenesis of IM is poorly understood. In the present study, we report the results of exome sequence analysis of two brothers diagnosed with visceral multicentric infantile myofibromatosis, and their healthy consanguineous parents. In the two brothers we identified novel homozygous variants in NDRG4 gene (N-myc downregulated gene family member 4) and in RLTPR gene (RGD motif, leucine rich repeats, tropomodulin domain and proline-rich containing). The healthy parents were heterozygous for both variants. Consistent with the phenotype of IM, NDRG4 is a tumor-related gene; its expression has been shown to be decreased in numerous tumor types, suggesting that it might be a tumor suppressor gene. Additionally, studies have demonstrated that NDRG4 may have a role in cell survival and tumor invasion. We thus propose that this homozygous variant in NDRG4 may be the causative variant of the autosomal recessive form of IM in the studied family and that it should be investigated in other cases of autosomal recessive infantile myofibromatosis.

A human immunodeficiency syndrome caused by mutations in CARMIL2

“…For family 2, we analysed the autosomal recessive CARMIL2 c.871+1G>T splice-site variant that had been reported as a WES finding20. We confirmed CARMIL2 c.871+1G>T by Sanger sequencing and found segregation with the disease phenotype (Fig.…”

“…Variants were annotated and their manifestation at the mRNA and protein level identified according to the Ensembl Database (version 68). In addition, information on variant frequencies was collected from HapMap (HM)38, 1000 genomes (TG)39, NHLBI Grand Opportunity Exome Sequencing Project (NH) and ExAC40.The WES approach for genomic DNA of family 2 subjects F2, M2, P2.1 and P2.2 has been published before20. The c.489insG and c.871+1G>T CARMIL2 mutations were confirmed by Sanger sequencing (see Supplemantary Table 5 for primer information).…”

NDRG4 hypermethylation is a potential biomarker for diagnosis and prognosis of gastric cancer in Chinese population

“…However, the research of NDRG4 variants in human cancers is scarce. A recent exome sequencing study [69] has identified that c.511G>C (p.Val171Leu), a novel NDRG4 homozygous variant, is associated with the autosomal recessive form of infantile myofibromatosis, showing that NDRG4 variations may play an important role in benign tumor. Future recent research on the interaction of genetic polymorphisms and epigenetic marks on NDRG4 gene might be useful to elaborate the role of this gene in gastric cancer risk.…”

Identification of novel hereditary cancer genes by whole exome sequencing

“…There is growing evidence that the recessive model of inheritance also plays a role in cancer susceptibility. Biallelic mutations have already been discovered for a number of rare cancer syndromes [34,48,91,94,96,156]. Modeling of inheritance suggests that patients with rare homozygous germline defects are unlikely to report family history [157], therefore the continuing emphasis on members of cancer families (Table 1) may further compromise the discovery of recessive genes.…”