title: Severe ipsilateral musculoskeletal involvement in a Cornelia de Lange patient with a novel NIPBL mutation.
abstract: Cornelia de Lange Syndrome (CdLS) is a congenital autosomal dominant (NIPBL, SMC3 and RAD21) or X-linked (SMC1A and HDAC8) disorder characterized by facial dysmorphism, pre and postnatal growth retardation, developmental delay and/or intellectual disability, and multiorgan involvement. Musculoskeletal malformations are usually bilateral and affect mainly the upper limbs; the range goes from brachyclinodactyly to severe reduction defects. Instead lower extremities are usually less and mildly involved. Here, we report on a 3-year-old Senegalese boy with typical craniofacial CdLS features, pre and postnatal growth retardation, atrial septal defect, developmental delay and right ipsilateral limb malformations, consistent with oligodactyly of the 3rd and 4th fingers, tibial agenesis and fibula hypoplasia. Exome sequencing and Sanger sequencing showed a novel missense mutation in NIPBL gene (c.6647A>G; p.(Tyr2216Cys)), which affects a conserved residue located within NIPBL HEAT repeat elements. Pyrosequencing analysis of NIPBL gene, disclosed similar levels of wild-type and mutated alleles in DNA and RNA samples from all tissues analyzed (oral mucosa epithelial cells, peripheral blood leukocytes and fibroblasts). These findings indicated the absence of somatic mosaicism, despite of the segmental asymmetry of the limbs, and confirmed biallelic expression for NIPBL transcripts, respectively. Additionally, conditions like Split-hand/foot malformation with long-bone deficiency secondary to duplication of BHLHA9 gene have been ruled out by the array-CGH and MLPA analysis. To our knowledge, this is the first CdLS patient described with major ipsilateral malformations of both the upper and lower extremities, that even though this finding could be due to a random event, expands the spectrum of limb reduction defects in CdLS.
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology- Physiology and Pediatrics, Medical School, University of Zaragoza, Spain; Department of Pediatrics, Hospital Pablo Tobón Uribe, Medellín, Colombia.
authors.forename: Carolina
authors.initials: C
authors.lastname: Baquero-Montoya
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology- Physiology and Pediatrics, Medical School, University of Zaragoza, Spain.
authors.forename: María-Concepción
authors.initials: MC
authors.lastname: Gil-Rodríguez
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology- Physiology and Pediatrics, Medical School, University of Zaragoza, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Hernández-Marcos
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology- Physiology and Pediatrics, Medical School, University of Zaragoza, Spain.
authors.forename: María-Esperanza
authors.initials: ME
authors.lastname: Teresa-Rodrigo
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology- Physiology and Pediatrics, Medical School, University of Zaragoza, Spain; Service of Pediatrics, Hospital Clínico Universitario "Lozano Blesa", Zaragoza, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Vicente-Gabas
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology- Physiology and Pediatrics, Medical School, University of Zaragoza, Spain.
authors.forename: María-Luisa
authors.initials: ML
authors.lastname: Bernal
authors.affiliation: Department of Molecular Biology, Sciences School, National University of Río Cuarto, Argentina.
authors.forename: Cesar-Horacio
authors.initials: CH
authors.lastname: Casale
authors.affiliation: Service of Pediatrics, Hospital Clínico Universitario "Lozano Blesa", Zaragoza, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Bueno-Lozano
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology- Physiology and Pediatrics, Medical School, University of Zaragoza, Spain; Service of Pediatrics, Hospital Clínico Universitario "Lozano Blesa", Zaragoza, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Bueno-Martínez
authors.affiliation: Cell Cycle Group, Cancer Epigenetics and Biology Program (PEBC), Institut d'Investigacions Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ethel
authors.initials: E
authors.lastname: Queralt
authors.affiliation: Quantitative Genomic Medicine Laboratories, Barcelona, Spain.
authors.forename: Olaya
authors.initials: O
authors.lastname: Villa
authors.affiliation: Quantitative Genomic Medicine Laboratories, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Hernando-Davalillo
authors.affiliation: Quantitative Genomic Medicine Laboratories, Barcelona, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Armengol
authors.affiliation: Molecular Modelling Group, Center of Molecular Biology ''Severo Ochoa'' (CSIC-UAM), Cantoblanco, Madrid, Spain.
authors.forename: Paulino
authors.initials: P
authors.lastname: Gómez-Puertas
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology- Physiology and Pediatrics, Medical School, University of Zaragoza, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Puisac
authors.affiliation: Pediatric Clinic, University of Milano Bicocca, San Gerardo Hospital, Monza, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology- Physiology and Pediatrics, Medical School, University of Zaragoza, Spain; Service of Pediatrics, Hospital Clínico Universitario "Lozano Blesa", Zaragoza, Spain.
authors.forename: Feliciano J
authors.initials: FJ
authors.lastname: Ramos
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology- Physiology and Pediatrics, Medical School, University of Zaragoza, Spain. Electronic address: juanpie@unizar.es.
authors.forename: Juan
authors.initials: J
authors.lastname: Pié
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins; D055028:Comparative Genomic Hybridization; D003635:De Lange Syndrome / Q000175:diagnosis* / Q000235:genetics*; D059472:Exome; D023061:Gene Order; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009139:Musculoskeletal Abnormalities / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D018797:Cell Cycle Proteins; C487465:NIPBL protein, human; D011506:Proteins
keywords: BHLHA9 duplication; CdLS; Cornelia de Lange Syndrome; Exome sequencing; HEAT repeat; Ipsilateral; Musculoskeletal involvement; NIPBL mutation