title: Genomic analysis of primordial dwarfism reveals novel disease genes.
abstract: Primordial dwarfism (PD) is a disease in which severely impaired fetal growth persists throughout postnatal development and results in stunted adult size. The condition is highly heterogeneous clinically, but the use of certain phenotypic aspects such as head circumference and facial appearance has proven helpful in defining clinical subgroups. In this study, we present the results of clinical and genomic characterization of 16 new patients in whom a broad definition of PD was used (e.g., 3M syndrome was included). We report a novel PD syndrome with distinct facies in two unrelated patients, each with a different homozygous truncating mutation in CRIPT. Our analysis also reveals, in addition to mutations in known PD disease genes, the first instance of biallelic truncating BRCA2 mutation causing PD with normal bone marrow analysis. In addition, we have identified a novel locus for Seckel syndrome based on a consanguineous multiplex family and identified a homozygous truncating mutation in DNA2 as the likely cause. An additional novel PD disease candidate gene XRCC4 was identified by autozygome/exome analysis, and the knockout mouse phenotype is highly compatible with PD. Thus, we add a number of novel genes to the growing list of PD-linked genes, including one which we show to be linked to a novel PD syndrome with a distinct facial appearance. PD is extremely heterogeneous genetically and clinically, and genomic tools are often required to reach a molecular diagnosis.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia;
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.forename: Eissa
authors.initials: E
authors.lastname: Faqeih
authors.forename: Shinu
authors.initials: S
authors.lastname: Ansari
authors.forename: Ghada
authors.initials: G
authors.lastname: Abdel-Salam
authors.forename: Zuhair N
authors.initials: ZN
authors.lastname: Al-Hassnan
authors.forename: Tarfa
authors.initials: T
authors.lastname: Al-Shidi
authors.forename: Rana
authors.initials: R
authors.lastname: Alomar
authors.forename: Sameera
authors.initials: S
authors.lastname: Sogaty
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001853:Bone Marrow / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics; D004392:Dwarfism / Q000235:genetics* / Q000473:pathology; D019066:Facies; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D009123:Muscle Hypotonia / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013131:Spine / Q000002:abnormalities* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C112203:CRIPT protein, human; D004268:DNA-Binding Proteins; C101467:XRCC4 protein, human