title: Contiguous mutation syndrome in the era of high-throughput sequencing.
abstract: We investigated two siblings, born to consanguineous parents, with neurological features reminiscent of adaptor protein complex 4 (AP4) deficiency, an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity, severe intellectual disability speech delay, microcephaly, and growth retardation. Yet, both children also presented with early onset obesity. Whole-exome sequencing identified two homozygous substitutions in two genes 170 kb apart on 7q22.1: a c.1137+1G>T splice mutation in AP4M1 previously described in a familial case of AP4-deficiency syndrome and the AZGP1 c.595A>T missense variant. Haplotyping analysis indicated a founder effect of the AP4M1 mutation, whereas the AZGP1 mutation arose more recently in our family. AZGP1 encodes an adipokine that stimulate lipolysis in adipocytes and regulates body weight in mice. We propose that the siblings' phenotype results from the combined effects of mutations in both AP4M1 and AZGP1 that account for the neurological signs and the morbid obesity of early onset, respectively. Contiguous gene syndromes are the consequence of loss of two or more adjacent genes sensible to gene dosage and the phenotype reflects a combination of endophenotypes. We propose to broaden this concept to phenotypes resulting from independent mutations in two genetically linked genes causing a contiguous mutation syndrome.
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital 75015, Paris, France.
authors.forename: Maéva
authors.initials: M
authors.lastname: Langouët
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital 75015, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Siquier-Pernet
authors.affiliation: Metabolic and Proteomic Biochemistry Service, Necker-Enfants Malades Hospital, AP-HP 75015, Paris, France.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Sanquer
authors.affiliation: Genomic Platform, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute 75015, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: Bioinformatic Platform, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute 75015, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital 75015, Paris, France ; Service de Radiologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP 75015, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital 75015, Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center 3015 CN, Rotterdam, The Netherlands.
authors.forename: Grazia M S
authors.initials: GM
authors.lastname: Mancini
authors.affiliation: Metabolic and Proteomic Biochemistry Service, Necker-Enfants Malades Hospital, AP-HP 75015, Paris, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Barouki
authors.affiliation: Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP 75015, Paris, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital 75015, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
keywords: AP4 deficiency syndrome; intellectual deficiency; obesity; whole-exome sequencing; zinc-α2-glycoprotein