MRX93 syndrome (BRWD3 gene): five new patients with novel mutations

Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders whose main characteristic is that either the weight, height, or head circumference are above the 97th centile or 2 to 3 SD above the mean for age and sex. Additional features, such as facial dysmorphism, developmental delay or intellectual disability (ID), congenital anomalies, neurological problems and an increased risk of neoplasia are usually associated with OGS. Genetic analysis in patients with overlapping clinical features is essential, to distinguish between two or more similar conditions, and to provide appropriate genetic counseling and recommendations for follow up. In the present paper, we report five new patients (from four unrelated families) with an X-linked mental retardation syndrome with overgrowth (XMR93 syndrome), also known as XLID-BRWD3-related syndrome. The main features of these patients include ID, macrocephaly and dysmorphic facial features. XMR93 syndrome is a recently described disorder caused by mutations in the Bromodomain and WD-repeat domain-containing protein 3 (BRWD3) gene. This article underscores the importance of genetic screening by exome sequencing for patients with OGS and ID with unclear clinical diagnosis, and expands the number of reported individuals with XMR93 syndrome, highlighting the clinical features of this unusual disease.Instituto de Salud Carlos III, Grant/Award Number: PI15/01481.Peer reviewe

A New Overgrowth Syndrome is due to Mutations in RNF125

Overgrowth syndromes (OGS) are a group of disorders in which all parameters of growth and physical development are above the mean for age and sex. We evaluated a series of 270 families from the Spanish Overgrowth Syndrome Registry with no known OGS. We identified one de novo deletion and three missense mutations in RNF125 in six patients from four families with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjögren syndrome. RNF125 encodes an E3 ubiquitin ligase and is a novel gene of OGS. Our studies of the RNF125 pathway point to upregulation of RIG-I-IPS1-MDA5 and/or disruption of the PI3K-AKT and interferon signaling pathways as the putative final effectors.Fil: Tenorio, Jair. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: Mansilla, Alicia. Instituto Cajal. Madrid; EspañaFil: Valencia, María. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: Martínez Glez, Víctor. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: Romanelli, Valeria. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; EspañaFil: Arias, Pedro. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: Castrejón, Nerea. Hospital San Juan de Dios. Barcelona; EspañaFil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas ; ArgentinaFil: Guillén Navarro, Encarna. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Hospital Virgen de la Arrixaca. Murcia; EspañaFil: Gordo, Gema. Universidad Autónoma de Madrid; EspañaFil: Mansilla, Elena. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: García Santiago, Fé. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: González Casado, Isabel. Hospital Universitario La Paz. Madrid; EspañaFil: Vallespín, Elena. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: Palomares, María. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: Mori, María A.. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: Santos Simarro, Fernando. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: García Miñaur, Sixto. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: Fernández, Luis. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: Mena, Rocío. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: Benito Sanz, Sara. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: del Pozo, Ángela. Hospital Universitario La Paz. Madrid; EspañaFil: Silla, Juan Carlos. Hospital Universitario La Paz. Madrid; EspañaFil: Ibañez, Kristina. Hospital Universitario La Paz. Madrid; EspañaFil: López Granados, Eduardo. Hospital Universitario La Paz. Madrid; EspañaFil: Martín Trujillo, Alex. Cancer Epigenetics and Biology Program. Barcelona; EspañaFil: Montaner, David. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Centro de Investigación Príncipe Felipe. Valencia; EspañaFil: The SOGRI Consortium. Hospital Universitario La Paz. Madrid; EspañaFil: Heath, Karen E. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Hospital Universitario La Paz. Madrid; EspañaFil: Campos Barros, Ángel. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Hospital Universitario La Paz. Madrid; EspañaFil: Dopazo, Joaquín. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Centro de Investigación Príncipe Felipe. Valencia; EspañaFil: Nevado, Julián. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Hospital Universitario La Paz. Madrid; EspañaFil: Monk, David. Cancer Epigenetics and Biology Program. Barcelona; EspañaFil: Ruiz Pérez, Víctor. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; EspañaFil: Lapunzina, Pablo. Centro de Investigación Biomédica en Red de Enfermedades Raras. Madrid; España. Universidad Autónoma de Madrid; Españ

Snijders Blok–Campeau Syndrome: Description of 20 Additional Individuals with Variants in <i>CHD3</i> and Literature Review

Snijders Blok–Campeau syndrome (SNIBCPS, OMIM# 618205) is an extremely infrequent disease with only approximately 60 cases reported so far. SNIBCPS belongs to the group of neurodevelopmental disorders (NDDs). Clinical features of patients with SNIBCPS include global developmental delay, intellectual disability, speech and language difficulties and behavioral disorders like autism spectrum disorder. In addition, patients with SNIBCPS exhibit typical dysmorphic features including macrocephaly, hypertelorism, sparse eyebrows, broad forehead, prominent nose and pointed chin. The severity of the neurological effects as well as the presence of other features is variable among subjects. SNIBCPS is caused likely by pathogenic and pathogenic variants in CHD3 (Chromodomain Helicase DNA Binding Protein 3), which seems to be involved in chromatin remodeling by deacetylating histones. Here, we report 20 additional patients with clinical features compatible with SNIBCPS from 17 unrelated families with confirmed likely pathogenic/pathogenic variants in CHD3. Patients were analyzed by whole exome sequencing and segregation studies were performed by Sanger sequencing. Patients in this study showed different pathogenic variants affecting several functional domains of the protein. Additionally, none of the variants described here were reported in control population databases, and most computational predictors suggest that they are deleterious. The most common clinical features of the whole cohort of patients are global developmental delay (98%) and speech disorder/delay (92%). Other frequent features (51–74%) include intellectual disability, hypotonia, hypertelorism, abnormality of vision, macrocephaly and prominent forehead, among others. This study expands the number of individuals with confirmed SNIBCPS due to pathogenic or likely pathogenic variants in CHD3. Furthermore, we add evidence of the importance of the application of massive parallel sequencing for NDD patients for whom the clinical diagnosis might be challenging and where deep phenotyping is extremely useful to accurately manage and follow up the patients