title: Exome sequencing identifies mutations in ABCD1 and DACH2 in two brothers with a distinct phenotype.
abstract: BACKGROUND
  We report on two brothers with a distinct syndromic phenotype and explore the potential pathogenic cause.
  
  
  METHODS
  Cytogenetic tests and exome sequencing were performed on the two brothers and their parents. Variants detected by exome sequencing were validated by Sanger sequencing.
  
  
  RESULTS
  The main phenotype of the two brothers included congenital language disorder, growth retardation, intellectual disability, difficulty in standing and walking, and urinary and fecal incontinence. To the best of our knowledge, no similar phenotype has been reported previously. No abnormalities were detected by G-banding chromosome analysis or array comparative genomic hybridization. However, exome sequencing revealed novel mutations in the ATP-binding cassette, sub-family D member 1 (ABCD1) and Dachshund homolog 2 (DACH2) genes in both brothers. The ABCD1 mutation was a missense mutation c.1126G > C in exon 3 leading to a p.E376Q substitution. The DACH2 mutation was also a missense mutation c.1069A > T in exon 6, leading to a p.S357C substitution. The mother was an asymptomatic heterozygous carrier. Plasma levels of very-long-chain fatty acids were increased in both brothers, suggesting a diagnosis of adrenoleukodystrophy (ALD); however, their phenotype was not compatible with any reported forms of ALD. DACH2 plays an important role in the regulation of brain and limb development, suggesting that this mutation may be involved in the phenotype of the two brothers.
  
  
  CONCLUSIONS
  The distinct phenotype demonstrated by these two brothers might represent a new form of ALD or a new syndrome. The combination of mutations in ABCD1 and DACH2 provides a plausible mechanism for this phenotype.
authors.affiliation: Department of Clinical Laboratory, the First Affiliated Hospital of Kunming Medical University, Yunnan Province, 650032, P R China. zylyh2007@163.com.
authors.forename: Yanliang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Prepotency Center, Dongguan Maternal and Child Health Hospital, Guangdong Province, 523000, P R China. 52745926@qq.com.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Clinical Laboratory, the First Affiliated Hospital of Kunming Medical University, Yunnan Province, 650032, P R China. liya0414@hotmail.com.
authors.forename: Ya
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Clinical Laboratory, the First Affiliated Hospital of Kunming Medical University, Yunnan Province, 650032, P R China. duanyong7@139.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Radiology Department, Dongguan Guanghua Hospital of Tongji Medical College, Guangdong Province, 523000, P R China. 873180492@qq.com.
authors.forename: Keyun
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Radiology Department, Dongguan Guanghua Hospital of Tongji Medical College, Guangdong Province, 523000, P R China. 75995629@qq.com.
authors.forename: Junwang
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Clinical Medical Research Center, Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Guangdong Province, 518020, P R China. daiyong2222@gmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D000013:Congenital Abnormalities / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins; D059472:Exome; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D035781:Siblings; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C403064:DACH2 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors