title: 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.
authors.affiliation: Laboratório de Genômica Clínica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Natália D
authors.initials: ND
authors.lastname: Linhares
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Maíra C M
authors.initials: MC
authors.lastname: Freire
authors.affiliation: Laboratório de Genômica Clínica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Raony G C C L
authors.initials: RG
authors.lastname: Cardenas
authors.affiliation: Laboratório Gene - Núcleo de Genética Médica, Belo Horizonte, Brazil.
authors.forename: Heloísa B
authors.initials: HB
authors.lastname: Pena
authors.affiliation: Divisão de Gastroenterologia Pediátrica, Hospital das Clínicas da UFMG, Belo Horizonte, Brazil.
authors.forename: Magda
authors.initials: M
authors.lastname: Bahia
authors.affiliation: Laboratório de Genômica Clínica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Laboratório Gene - Núcleo de Genética Médica, Belo Horizonte, Brazil. Electronic address: spena@dcc.ufmg.br.
authors.forename: Sergio D J
authors.initials: SD
authors.lastname: Pena
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D004252:DNA Mutational Analysis; D059472:Exome; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D018224:Myofibromatosis / Q000151:congenital* / Q000000981:diagnostic imaging / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014463:Ultrasonography
chemical_list: D009124:Muscle Proteins; C431705:NDRG4 protein, human; D009419:Nerve Tissue Proteins
keywords: Congenital generalized fibromatosis; Exome sequencing; Myofibromatosis; NDRG4 gene; Neoplasms