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MEIS2 Gene Is Responsible for Intellectual Disability, Cardiac

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MEIS2 Gene Is Responsible for Intellectual Disability, Cardiac European Journal of Medical Genetics 63 (2020) 103627 Contents lists available at ScienceDirect European Journal of Medical Genetics journal homepage: www.elsevier.com/locate/ejmg MEIS2 gene is responsible for intellectual disability, cardiac defects and a T distinct facial phenotype Annarita Gilibertia,b,1, Aurora Curròa,b,1, Filomena Tiziana Papaa, Elisa Frullantia, ∗ Francesca Ariania,b, Gianni Coriolanic, Salvatore Grossoc, Alessandra Renieria,b, , Francesca Maria,b a Medical Genetics, University of Siena, Siena, Italy b Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy c Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Siena, Italy ARTICLE INFO ABSTRACT Keywords: Myeloid ecotropic insertion site 2 (MEIS2) gene, encoding a homeodomain-containing transcription factor, has Ventricular septal defect been recently related to syndromic intellectual disability with cleft palate and cardiac defects. Here, we present a Intellectual disability male patient, aged 10, with cardiac defects, intellectual disability, facial dysmorphisms and gastroesophageal Exome analysis reflux. Whole exome sequencing revealed a novel de novo nonsense mutation inthe MEIS2 gene. This patient MEIS2 represents another reported case with a de novo MEIS2 point mutation and helps to characterize a distinct facial phenotype consisting in low anterior hairline, thin eyebrows, anteverted nares, hypoplastic alae nasi, and M- shape upper lip. Furthermore, these data confirm the role of this gene in cardiac, nervous system development and gastrointestinal function. 1. Introduction novo MEIS2 point mutation and propose that a distinct facial phenotype is present in these patients making the MEIS2-related condition a dis- Myeloid ecotropic insertion site 2 (MEIS2) gene (OMIM # 600987) tinct and recognizable neurodevelopmental disorder. encodes a homeodomain-containing transcription factor belonging to the TALE (three amino acid loop extension) highly conserved super- 2. Materials and methods family of transcription regulators. Recent studies identified MEIS2 as a gene essential for cranial and cardiac neural crest development 2.1. Sample and DNA extraction (Machon et al., 2015). The first evidences of MEIS2 involvement in syndromic ID date back to 2007 when a unique case with intellectual Parents provided and signed a written informed consent at the disability (ID), atrial septal defect type secundum and cleft palate and a Medical Genetics Unit of the Azienda Ospedaliera Universitaria Senese, 15q14 microdeletion including MEIS2 was reported (Erdogan et al., Siena, Italy, for exome sequencing analysis, clinical data usage, and the 2007). Subsequently additional few patients with a copy number var- use of DNA samples from the tested individuals for both diagnostic and iation including MEIS2, either partially or totally together with flanking research purposes. Genomic DNA was extracted from EDTA peripheral genes, were reported, indicating that MEIS2 was the phenotype causa- blood samples using MagCore HF16 (Diatech Lab Line, Jesi, Ancona, tive gene (Chen et al., 2008; Crowley et al., 2010; Johansson et al., Italy). 2014; Gambin et al., 2017; Shimojima et al., 2017; Brunetti-Pierri et al., 2008; Conte et al., 2016). Very recently, additional de novo MEIS2 2.2. Whole Exome Sequencing point mutations have been described in patients with ID, palate ab- normalities, congenital heart defect, and facial dysmorphisms (Louw Exome sequencing was performed on genomic DNA samples of et al., 2015; Fujita et al., 2016; Srivastava et al., 2018; Douglas et al., proband and both parents. The library preparation was performed using 2018; Verheije et al., 2018). Here, we present another patient with a de the Ion AmpliSeq™ Exome Kit that allows to target ∼33 Mb of coding ∗ Corresponding author. Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. E-mail address: [email protected] (A. Renieri). 1 These authors contributed equally to the work. https://doi.org/10.1016/j.ejmg.2019.01.017 Received 7 August 2018; Received in revised form 25 January 2019; Accepted 29 January 2019 Available online 05 February 2019 1769-7212/ © 2019 Elsevier Masson SAS. All rights reserved. A. Giliberti, et al. European Journal of Medical Genetics 63 (2020) 103627 Fig. 1. Pictures of our patient and the first two reported patients with a MEIS2 point mutation. A) Present patient B) Patient reported by Fujita et al. C) Patient reported by Louw et al. Permission for reproduction of the pictures of the two already published cases has been asked to the Publishing Company. exons plus 15 Mb of flanking regions for a total of ∼58 Mb, intotal specific primer pairs (Forward 5′-AGACATCACACTGTTGCTCTT-3’; more than 97% of the coding regions as described by Consensus Coding Reverse 5-’AGACCCCAAAAGAGACGGAG-3′) and PCR products were Sequences (CCDS) annotation, using 12 primer pools for highly specific sequenced employing ABIPRISM3130 Genetic Analyzer (Applied enrichment of exons within the human genome. Taking advantage of a Biosystems, Foster City, CA, USA) and data were analyzed with barcode system, three samples were loaded together in a single run and Sequencher software V.4.9 (Gene Codes, Ann Arbor, USA). sequenced. Exome sequencing was performed using the Life Technologies Ion Proton sequencer (Life Technologies). Data analysis 2.4. Mutation nomenclature was performed with Torrent SuitetTM Software v3.6.2. The provider generated at least 30X effective mean depth per sample. Using specific The mutation is described according to Human Genome Variations parameters we obtained removing adaptors contamination and low Society (HGVS) (den Dunnen, 2016 #195). Nucleotide numbers are quality sequences, so the total amount of clean data was mapped to the derived from the cDNA sequence of MEIS2 (GenBank accession no. NM_ UCSC/hg19 reference genome. Indel and variants calls were made using 170674.4). GATK version 2.7 (and recommended parameters) (McKenna et al., 2010)and then the variants were also annotated against external da- tasets including 1000 genomes and dbSNP. 3. Results Prioritization of the variants was obtained selecting frameshift, splice, stopgain or stoploss mutations, missense variants predicted to be 3.1. Clinical description damaging by CADD-phred prediction tools and variants with minor allele frequency (MAF) < 0,01. Here we present a caucasian male patient, aged 10, evaluated in our Unit because of intellectual disability. Parents are not consanguineous and aged 28 years (mother) and 29 years (father) at the time of de- 2.3. Sanger sequencing livery. He was born at 37 gws with cesarean section; his weight was 2540 g (−0.9 SD), his length was 47 cm (−0.53 SD), his occipital Sanger sequencing was performed in the proband and his parents. frontal circumference (OFC) was 31,8 cm (−1.58 SD), and the APGAR DNA was amplified by PCR on exon 6 of MEIS2 (NM_170674.4) using index was 8–10. He had a history of ventricular and atrial septal defect 2 A. Giliberti, et al. European Journal of Medical Genetics 63 (2020) 103627 Fig. 2. MEIS2 point mutations. Upper panel (A): Mutation confirmation and segregation analysis by Sanger sequencing. Lower panel (B): Scheme oftheMEIS2 protein with the localization of the mutation reported in this paper. that solved without surgery and undescended right testicle. He had 4. Discussion psychomotor delay: he reached trunk control at 12 months, he was able to walk after 18 months, to speak at 5 years; he got sphincter control We report on a patient carrying a de novo nonsense mutation in after the age of 5 years. We evaluated the patient for the first time when MEIS2, a gene previously associated with syndromic ID (Johansson he was 8 years old: he was 133 cm tall (0.06 SD), his weight was et al., 2014; Louw et al., 2015; Douglas et al., 2018; Verheije et al., 34,4 Kg (1.03 SD) and his OFC was 55 cm (2 SD); he had large forehead, 2018). Cardiac defects, palate anomalies and gastroesophageal dis- low frontal hairline, thick hair, thin and laterally extended eyebrows, turbances are among the most frequent comorbidities (Johansson et al., large nasal tip with anteverted and hypoplastic nostrils, M-shaped 2014; Louw et al., 2015; Fujita et al., 2016; Douglas et al., 2018; upper lip, high palate, tapering fingers, sandal gap bilaterally (Fig. 1A). Verheije et al., 2018). Till now 47 unrelated patients with MEIS2 mu- His language was very poor and repetitive, and he had stereotyping tations have been described. The majority of these patients have been movements. He had a IQ of 45 (according to a WISC-IV scale), and he identified by array-CGH analysis and carried different microdeletions was diagnosed with Autism Spectrum Disorder (ASD). He also pre- involving MEIS2. In four patients the microdeletion either interrupted sented stereotypic hand and trunk movements. In particular, he showed the gene or involved uniquely the MEIS2 gene, pointing to this gene as clenched fists held close while rocking the trunk. His EEG had nopat- the major gene responsible for the phenotype. tern anomalies; the most recent brain MRI detected ectasia and gliosis Here, we describe another patient bearing a MEIS2 point mutation of Virchow-Robin areas. He had no anomalies at US evaluation of the (Table 1). abdomen nor at an evaluation of the anterior eye chamber and fundus Pathogenic sequence changes reported to date include six truncating oculi. A cardiac US confirmed the presence of VSD. He was previously mutation, six missense mutation, three splice variants and one in-frame investigated for Fragile-X, with a negative result. A previous array-CGH deletion (Fujita et al., 2016; Srivastava et al., 2018; Louw et al., 2015; analysis revealed a small 19q13.12 microdeletion paternally inherited Douglas et al., 2018; Verheije et al., 2018). All patients except one of not including known disease genes, specifically arr [GRCh37] 19q13.12 those reported by Verheije et al., who was diagnosed by targeted se- (42595081_42744350)×1. quencing of MEIS2, have been identified by whole exome analysis, suggesting that the phenotype associated with MEIS2 point mutations is not yet easily recognizable (Verheije et al., 2018).
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