title: Sacral agenesis: a pilot whole exome sequencing and copy number study.
abstract: BACKGROUND
  Caudal regression syndrome (CRS) or sacral agenesis is a rare congenital disorder characterized by a constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. CRS is a complex condition, attributed to an abnormal development of the caudal mesoderm, likely caused by the effect of interacting genetic and environmental factors. A well-known risk factor is maternal type 1 diabetes.
  
  
  METHODS
  Whole exome sequencing and copy number variation (CNV) analyses were conducted on 4 Caucasian trios to identify de novo and inherited rare mutations.
  
  
  RESULTS
  In this pilot study, exome sequencing and copy number variation (CNV) analyses implicate a number of candidate genes, including SPTBN5, MORN1, ZNF330, CLTCL1 and PDZD2. De novo mutations were found in SPTBN5, MORN1 and ZNF330 and inherited predicted damaging mutations in PDZD2 (homozygous) and CLTCL1 (compound heterozygous). Importantly, predicted damaging mutations in PTEN (heterozygous), in its direct regulator GLTSCR2 (compound heterozygous) and in VANGL1 (heterozygous) were identified. These genes had previously been linked with the CRS phenotype. Two CNV deletions, one de novo (chr3q13.13) and one homozygous (chr8p23.2), were detected in one of our CRS patients. These deletions overlapped with CNVs previously reported in patients with similar phenotype.
  
  
  CONCLUSIONS
  Despite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients.
authors.affiliation: Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Porsch
authors.affiliation: Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Merello
authors.affiliation: Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: De Marco
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.
authors.forename: Guo
authors.initials: G
authors.lastname: Cheng
authors.affiliation: AbaCid-Genética. Grupo HM Hospitales, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Rodriguez
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.
authors.forename: Manting
authors.initials: M
authors.lastname: So
authors.affiliation: Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.|Centre for Reproduction, Development, and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.|Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.|State Key Laboratory of Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.
authors.forename: Pak C
authors.initials: PC
authors.lastname: Sham
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.|Centre for Reproduction, Development, and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Tam
authors.affiliation: Istituto Giannina Gaslini, Genoa, Italy. valeriacapra@ospedale-gaslini.ge.it.
authors.forename: Valeria
authors.initials: V
authors.lastname: Capra
authors.affiliation: Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.|Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.|State Key Laboratory of Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR. mmgarcia@hku.hk.|Centre for Reproduction, Development, and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR. mmgarcia@hku.hk.|The Hong Kong Jockey Club Building for Interdisciplinary Research, 5 Sassoon Road, Pokfulam, Hong Kong, People's Republic of China. mmgarcia@hku.hk.
authors.forename: Maria-Mercè
authors.initials: MM
authors.lastname: Garcia-Barcelo
authors.affiliation: Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR. ddc123@hku.hk.|Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR. ddc123@hku.hk.
authors.forename: Desmond D
authors.initials: DD
authors.lastname: Campbell
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D015815:Cell Adhesion Molecules; D033922:Clathrin Heavy Chains / Q000235:genetics; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D056915:DNA Copy Number Variations; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008588:Meningocele / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics; D010641:Phenotype; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D012445:Sacrococcygeal Region / Q000002:abnormalities* / Q000473:pathology; D017422:Sequence Analysis, DNA
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101272:CLTCL1 protein, human; D015815:Cell Adhesion Molecules; D009363:Neoplasm Proteins; C423943:PDZD2 protein, human; D033922:Clathrin Heavy Chains; D004247:DNA
keywords: Caudal regression; Copy-number variation; Sacral agenesis; Whole exome sequencing