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      Primary Dwarfism, Microcephaly, and Chorioretinopathy due to a PLK4 Mutation in Two Siblings

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          Introduction: Primary autosomal recessive microcephalies (MCPHs) are characterized by primary dwarfism with MCPH and may present delayed psychomotor development and visual impairment. Biallelic loss of function variants in the PLK4 gene , which encodes the polo-like kinase 4 protein involved in centriole biogenesis, has been recently identified in several patients with MCPH and various ethnic backgrounds. Case Presentation: Here, we describe 2 siblings of different sex from Equatorial Guinea harboring a homozygous frameshift mutation in PLK4 (c.1299_1303del, p.Phe433Leufs*6). A Seckel syndrome spectrum phenotype was present in both siblings, with short stature, severe MCPH, reduced brain volume, and distinctive facial features. They also presented severe intellectual disability, lissencephaly/pachygyria, subependymal heterotopia, and ophthalmological impairment. One of them suffered from deafness, and scoliosis was observed in the other. Discussion/Conclusion: Biallelic variants in PLK4 lead to a syndrome where severe short stature, MCPH, and cognitive impairment are constant features. However, ocular, skeletal, and other neurological manifestations can vary upon the same genetic basis.

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          Most cited references 18

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          Is Open Access

          Genetic Mapping and Exome Sequencing Identify Variants Associated with Five Novel Diseases

          The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb) that contain many genes (mean = 79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.
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            Novel compound heterozygous variants in PLK4 identified in a patient with autosomal recessive microcephaly and chorioretinopathy

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              Genetic causes of growth disorders

               J Argente (2020)

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                April 2021
                23 March 2021
                : 93
                : 9-10
                : 567-572
                aDepartments of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Research Institute “La Princesa,”, Madrid, Spain
                bDepartment of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
                cCentro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutriciόn (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
                dDepartment of Clinical Genetics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
                eGenetics Unit, Universitat Pompeu Fabra, Barcelona, Spain
                fHospital del Mar Research Institute (IMIM), Barcelona, Spain
                gCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
                hWomen’s and Children’s Hospital, South Australian Health and Medical Research Institute (SAHMRI), The University of Adelaide, Adelaide, South Australia, Australia
                iIMDEA, Food Institute, CEIUAM+CSI, Cantoblanco, Madrid, Spain
                Author notes
                *Jesús Argente, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Avda. Menéndez Pelayo, 65, ES–28009 Madrid (Spain), jesus.argente@uam.es
                514280 Horm Res Paediatr 2020;93:567–572
                © 2021 S. Karger AG, Basel

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                Page count
                Figures: 1, Tables: 1, Pages: 6
                Novel Insights from Clinical Practice / Case Report


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