title: Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome.
abstract: MED13L haploinsufficiency has recently been described as responsible for syndromic intellectual disability. We planned a search for causative gene variants in seven subjects with intellectual disability and overlapping dysmorphic facial features such as bulbous nasal tip, short mouth and straight eyebrows. We found two de novo frameshift variants in MED13L, consisting in single-nucleotide deletion (c.3765delC) and duplication (c.607dupT). A de novo nonsense variant (c.4420A>T) in MED13L was detected in a further subject in the course of routine whole-exome sequencing. By analyzing the clinical data of our patients along with those recently described in the literature, we confirm that there is a common, recognizable phenotype associated with MED13L haploinsufficiency, which includes intellectual disability and a distinctive facial appearance. Congenital heart diseases are found in some subjects with various degree of severity. Our observation of cleft palate, ataxia, epilepsy and childhood leukemia observed in single cases broadens the known clinical spectrum. Haploinsufficiency for MED13L should be considered in the differential diagnosis of the 1p36 microdeletion syndrome, due to overlapping dysmorphic facial features in some patients. The introduction of massive parallel-sequencing techniques into clinical practice is expected to allow for detection of other causative point variants in MED13L. Analysis of genomic data in connection with deep clinical evaluation of patients could elucidate genetic heterogeneity of the MED13L haploinsufficiency phenotype.
authors.affiliation: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Cafiero
authors.affiliation: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Marangi
authors.affiliation: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Orteschi
authors.affiliation: Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, USA.
authors.forename: Marwan
authors.initials: M
authors.lastname: Ali
authors.affiliation: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Asaro
authors.affiliation: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ponzi
authors.affiliation: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Moncada
authors.affiliation: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ricciardi
authors.affiliation: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Murdolo
authors.affiliation: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Mancano
authors.affiliation: Istituto di Neuropsichiatria Infantile, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Contaldo
authors.affiliation: Istituto di Psichiatria e Neuropsichiatria Infantile, Università La Sapienza, Roma, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leuzzi
authors.affiliation: Istituto di Neuropsichiatria Infantile, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Battaglia
authors.affiliation: Istituto di Neuropsichiatria Infantile, Università Cattolica Sacro Cuore, Roma, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Mercuri
authors.affiliation: Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Slavotinek
authors.affiliation: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Zollino
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002972:Cleft Palate / Q000235:genetics / Q000503:physiopathology; D019066:Facies; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D018740:Genetic Heterogeneity; D057895:Haploinsufficiency / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D056892:Mediator Complex / Q000235:genetics*; D010641:Phenotype; D017384:Sequence Deletion
chemical_list: C480067:MED13L protein, human; D056892:Mediator Complex