Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature.

Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type. Next-generation sequencing (NGS) has aided the identification of heterozygous ACAN mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis. This study involves clinical and genetic characterization of 16 probands with heterozygous ACAN variants, 14 with short stature and mild skeletal defects (group 1) and two with SEDK (group 2). Subsequently, we reviewed the literature to determine the frequency of the different clinical characteristics in ACAN-positive individuals. A total of 16 ACAN variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS). Interestingly, brachydactyly was observed in all probands. Probands from group 1 with a pathogenic mutation tended to be shorter, and 60% had an advanced BA compared to 0% in those with a VUS. A higher incidence of coxa valga was observed in individuals with a VUS (37% vs 0%). Nevertheless, other features were present at similar frequencies. ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia. It is also important to note that advanced BA and osteoarticular complications are not obligatory conditions for aggrecanopathies/aggrecan-associated dysplasias

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

CLAPO syndrome: identification of somatic activating PIK3CA mutations and delineation of the natural history and phenotype

[Purpose]: CLAPO syndrome is a rare vascular disorder characterized by capillary malformation of the lower lip, lymphatic malformation predominant on the face and neck, asymmetry, and partial/generalized overgrowth. Here we tested the hypothesis that, although the genetic cause is not known, the tissue distribution of the clinical manifestations in CLAPO seems to follow a pattern of somatic mosaicism.[Methods]: We clinically evaluated a cohort of 13 patients with CLAPO and screened 20 DNA blood/tissue samples from 9 patients using high-throughput, deep sequencing.[Results]: We identified five activating mutations in the PIK3CA gene in affected tissues from 6 of the 9 patients studied; one of the variants (NM_006218.2:c.248T>C; p.Phe83Ser) has not been previously described in developmental disorders.[Conclusion]: We describe for the first time the presence of somatic activating PIK3CA mutations in patients with CLAPO. We also report an update of the phenotype and natural history of the syndrome.This research was supported by the project “Genetics of vascular and lymphatic malformations” financed with funds donated by Asociación Ultrafondo and Villareal FC, cofinanced by project IP-17 from the funding call “Todos Somos Raros” (Telemaraton TVE promoted by Fundación Isabel Gemio, Federación ASEM, and Federación Española de Enfermedades Raras), cofinanced by the Instituto de Salud Carlos III, FEDER FUNDS FIS PI15/01481, and IIS-Fundación Jiménez Díaz UAM Genome Medicine Chair.Peer reviewe

PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13.3 microdeletion/microduplication syndrome

Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the identification of novel imbalances in individuals with intellectual disability (ID), autistic disorders and congenital malformations. Here we report a \u27genotype first\u27 approach using aCGH on 13 unrelated patients with 19p13.3 submicroscopic rearrangement (11 deletions and 2 duplications) and review cases in the literature and in public databases. Shared phenotypic features suggest that these patients represent an interstitial microdeletion/microduplication syndrome at 19p13.3. Common features consist of abnormal head circumference in most patients (macrocephaly with the deletions and microcephaly with the duplications), ID with developmental delay (DD), hypotonia, speech delay and common dysmorphic features. The phenotype is associated with at least a ~0.113 Mb critical region harboring three strong candidate genes probably associated with DD, ID, speech delay and other dysmorphic features: MAP2K2, ZBTB7A and PIAS4, an E3 ubiquitin ligase involved in the ubiquitin signaling pathways, which we hypothesize for the first time to be associated with head size in humans