title: Expanding the phenotype of RTTN variations: a new family with primary microcephaly, severe growth failure, brain malformations and dermatitis.
abstract: Primary autosomal recessive microcephaly (MCPH) is a developmental disorder characterized by prenatal onset of abnormal brain growth. MCPH occurs both alone and as part of a broad range of neurodevelopmental syndromes with or without cortical malformations and growth retardation. Here we report a consanguineous Moroccan family with two siblings affected by severe primary microcephaly, failure to thrive, congenital dermatitis and severe developmental delay. Brain magnetic resonance imaging showed lissencephaly of frontal lobes and periventricular heterotopia of the gray matter. We performed both Comparative Genomic Hybridization array and whole exome sequencing (WES) analyses of the kindred. No quantitative defects were detected. However, WES identified a new homozygous missense variation in the penultimate nucleotide of exon 23 of RTTN gene (c.2953A>G;pArg985Gly). cDNA sequencing revealed two abnormal spliced products, one lacking only exon 23 and the other lacking exons 22 and 23 (out-of-frame). RTTN is a protein involved in cilia structure and function. Homozygous mutations in RTTN gene have been described in bilateral diffuse isolated polymicrogyria and, more recently, in microcephalic primordial dwarfism (PD). We found a novel homozygous mutation in RTTN associated with microcephalic PD as well as complex brain malformations and congenital dermatitis, thus expanding the phenotypic spectrum of both RTTN-associated diseases and ciliary dysfunction.
authors.affiliation: Dipartimento della Donna, del Bambino, di Chirurgia Generale e Specialistica, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Grandone
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, Naples, Italy.|Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (NA), Italy.
authors.forename: A
authors.initials: A
authors.lastname: Torella
authors.affiliation: Dipartimento della Donna, del Bambino, di Chirurgia Generale e Specialistica, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Santoro
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Giugliano
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Del Vecchio Blanco
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (NA), Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mutarelli
authors.affiliation: Dipartimento di Scienze Mediche, Chirurgiche, Neurologiche, Metaboliche e dell'Invecchiamento, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cirillo
authors.affiliation: Dipartimento della Donna, del Bambino, di Chirurgia Generale e Specialistica, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Cirillo
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Piluso
authors.affiliation: Dipartimento della Donna, del Bambino, di Chirurgia Generale e Specialistica, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Capristo
authors.affiliation: Dipartimento della Donna, del Bambino, di Chirurgia Generale e Specialistica, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Festa
authors.affiliation: Dipartimento della Donna, del Bambino, di Chirurgia Generale e Specialistica, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Marzuillo
authors.affiliation: Dipartimento della Donna, del Bambino, di Chirurgia Generale e Specialistica, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Miraglia Del Giudice
authors.affiliation: Dipartimento della Donna, del Bambino, di Chirurgia Generale e Specialistica, Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Perrone
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, Naples, Italy. vinnigro@gmail.com, vincenzo.nigro@unina2.it.|Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (NA), Italy. vinnigro@gmail.com, vincenzo.nigro@unina2.it.
authors.forename: V
authors.initials: V
authors.lastname: Nigro
mesh_terms: D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D055028:Comparative Genomic Hybridization; D003241:Consanguinity; D003872:Dermatitis / Q000235:genetics* / Q000503:physiopathology; D005091:Exons / Q000235:genetics; D005260:Female; D006130:Growth Disorders / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D006720:Homozygote; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D010375:Pedigree; D010641:Phenotype
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C576561:RTTN protein, human
keywords: brain malformation; lissencephaly; primary cilium; primary microcephaly; primordial dwarfism; rotatin