title: ATRX mutation in two adult brothers with non-specific moderate intellectual disability identified by exome sequencing.
abstract: In this report, we describe two adult brothers affected by moderate non-specific intellectual disability (ID). They showed minor facial anomalies, not clearly ascribable to any specific syndromic patterns, microcephaly, brachydactyly and broad toes. Both brothers presented seizures. Karyotype, subtelomeric and FMR1 analysis were normal in both cases. We performed array-CGH analysis that revealed no copy-number variations potentially associated with ID. Subsequent exome sequence analysis allowed the identification of the ATRX c.109C>T (p.R37X) mutation in both the affected brothers. Sanger sequencing confirmed the presence of the mutation in the brothers and showed that the mother is a healthy carrier. Mutations in the ATRX gene cause the X-linked alpha thalassemia/mental retardation (ATR-X) syndrome (MIM #301040), a severe clinical condition usually associated with profound ID, facial dysmorphism and alpha thalassemia. However, the syndrome is clinically heterogeneous and some mutations, including the c.109C>T, are associated with a broad phenotypic spectrum, with patients displaying a less severe phenotype with only mild-moderate ID. In the case presented here, exome sequencing provided an effective strategy to achieve the molecular diagnosis of ATR-X syndrome, which otherwise would have been difficult to consider due to the mild non-specific phenotype and the absence of a family history with typical severe cases.
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Moncini
authors.affiliation: UOD Genetica Medica, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: M F
authors.initials: MF
authors.lastname: Bedeschi
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Castronovo
authors.affiliation: Laboratorio di Citogenetica Medica e Genetica Molecolare, Istituto Auxologico Italiano, Cusano Milanino (MI), Italy.
authors.forename: M
authors.initials: M
authors.lastname: Crippa
authors.affiliation: UOD Genetica Medica, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Calvello
authors.affiliation: IRCCS "E Medea", Bosisio Parini, Lecco, Centro di Riabilitazione "La nostra Famiglia" Sesto San Giovanni, Italy.
authors.forename: R R
authors.initials: RR
authors.lastname: Garghentino
authors.affiliation: UOD Genetica Medica, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Scuvera
authors.affiliation: Laboratorio di Citogenetica Medica e Genetica Molecolare, Istituto Auxologico Italiano, Cusano Milanino (MI), Italy.
authors.forename: P
authors.initials: P
authors.lastname: Finelli
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Venturin
keywords: ATR-X syndrome; ATRX mutation; Exome sequencing; Intellectual disability; Non-specific phenotype