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Fresno, CA, United States

Gripp K.W.,DuPont Company | Curry C.,University of California at San Francisco | Olney A.H.,University of Nebraska Medical Center | Sandoval C.,New York Medical College | And 6 more authors.
American Journal of Medical Genetics, Part A

Patients with physical findings suggestive of Treacher Collins syndrome (TCS) or mandibulofacial dysostosis (MFD) and macrocytic anemia diagnostic of Diamond-Blackfan anemia (DBA) have been reported. Disease-causing genes have been identified for TCS and other MFDs. Mutations in several ribosomal protein genes and the transcription factor GATA1 result in DBA. However, no disease-causing mutation had been identified in the reported patients with the combination of TCS/MFD and DBA phenotype, and we hypothesized that pathogenic mutations in a single gene could be identified using whole exome analysis. We studied probands from six unrelated families. Combining exome analysis and Sanger sequencing, we identified likely pathogenic mutations in 5/6 families. Two mutations in unrelated families were seen in RPS26, the known DBA10 gene. One variant was predicted to affect mRNA splicing, and the other to lead to protein truncation. In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26. De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene. We conclude that the phenotype combining features of TCS with DBA is genetically heterogeneous. Each of the pathogenic variants identified is predicted to impede ribosome biogenesis, which in turn could result in altered cell growth and proliferation, causing abnormal embryologic development, defective erythropoiesis and reduced growth. The phenotype combining TCS/MFD and DBA is highly variable, overlaps with DBA and lies within the phenotypic spectrum of ribosomopathies. © 2014 Wiley Periodicals, Inc. Source

Myers A.,Stanford University | Bernstein J.A.,Stanford University | Brennan M.-L.,Stanford University | Curry C.,Genetic Medicine Central California | And 11 more authors.
American Journal of Medical Genetics, Part A

The RASopathies are a family of developmental disorders caused by heritable defects of the RAS/MAPK signaling pathway. While the postnatal presentation of this group of disorders is well known, the prenatal and neonatal findings are less widely recognized. We report on the perinatal presentation of 10 patients with Noonan syndrome (NS), nine with Cardiofaciocutaneous syndrome (CFCS) and three with Costello syndrome (CS), in conjunction with the results of a comprehensive literature review. The majority of perinatal findings in NS, CS, and CFCS are shared: polyhydramnios; prematurity; lymphatic dysplasia; macrosomia; relative macrocephaly; respiratory distress; hypotonia, as well as cardiac and renal anomalies. In contrast, fetal arrhythmia and neonatal hypoglycemia are relatively specific to CS. NS, CS, and CFCS should all be considered as a possible diagnosis in pregnancies with a normal karyotype and ultrasound findings of a RASopathy. Recognition of the common perinatal findings of these disorders should facilitate both their prenatal and neonatal diagnosis. © 2014 Wiley Periodicals, Inc. Source

Marcadier J.L.,Childrens Hospital of Eastern Ontario | Mears A.J.,University of Ottawa | Woods E.A.,Community Perinatology Medical Group | Fisher J.,Genetic Medicine Central California | And 7 more authors.
American Journal of Medical Genetics, Part A

PDAC (also termed Matthew Wood) syndrome is a rare, autosomal recessive disorder characterized by pulmonary hypoplasia/aplasia, diaphragmatic defects, bilateral anophthalmia, and cardiac malformations. The disorder is caused by mutations in STRA6, an important regulator of vitamin A and retinoic acid metabolism. We describe six cases from four families of Hmong ancestry, seen over a 30 years period in California. These include: (i) consanguineous siblings with a combination of bilateral anophthalmia, diaphragmatic abnormalities, truncus arteriosus, and/or pulmonary agenesis/hypoplasia; (ii) a singleton fetus with bilateral anophthalmia, pulmonary agenesis, cardiac malformation, and renal hypoplasia; (iii) a sibling pair with a combination of antenatal contractures, camptodactyly, fused palpebral fissures, pulmonary agenesis, and/or truncus arteriosus; (iv) a fetus with bilateral anophthalmia, bushy eyebrows, pulmonary agenesis, heart malformation, and abnormal hand positioning. The phenotypic spectrum of PDAC syndrome has until now not included contractures or camptodactyly. Sequencing of STRA6 in unrelated members of families three and four identified a novel, shared homozygous splice site alteration (c.113+3_4delAA) that is predicted to be pathogenic. We hypothesize this may represent a unique disease allele in the Hmong. We also provide a focused review of all published PDAC syndrome cases with confirmed or inferred STRA6 mutations, illustrating the phenotypic and molecular variability that characterizes this disorder. © 2015 Wiley Periodicals, Inc. Source

Bolling M.C.,University of Groningen | Veenstra M.J.,University of Groningen | Jonkman M.F.,University of Groningen | Diercks G.F.H.,University of Groningen | And 5 more authors.
British Journal of Dermatology

Desmoplakin is the major linker in desmosomes in epithelia and myocardium, anchoring intermediate filaments by the C-terminus to plakoglobin and plakophilin in the desmosomal plaque. Mutations in the gene DSP encoding desmoplakin have been associated with various phenotypes affecting skin and/or heart. One of these phenotypes, lethal acantholytic epidermolysis bullosa (LAEB), is characterized by extensive postnatal shedding of epidermis leading to early demise and is caused by recessive mutations in the gene DSP resulting in truncation of the desmoplakin C-terminus. Here we describe two infants born to the same consanguinous parents who suffered extensive epidermal dislodgment and died shortly after birth. In addition, universal alopecia, anonychia, malformed ears and cardiomyopathy were observed. As the clinical diagnosis was LAEB, DSP mutation analysis was performed. A homozygous deletion (c.2874del5) abrogating the donor splice site of exon 20 was found. The deletion is predicted to cause read-through in intron 20 with subsequent recognition of a premature termination codon, resulting in desmoplakin lacking its rod domain and C-terminus (p.Lys959MetfsX5). Electron microscopic analysis of skin biopsies showed absence of the desmosomal inner dense plaque and lack of tonofilament insertion. This is the second report of LAEB. These findings suggest DSP mutations as the aetiology of LAEB and cardiomyopathy as part of the phenotype. Furthermore, they indicate that in addition to the desmoplakin C-terminus, the rod domain is dispensable for intrauterine development but is essential for the inner dense plaque of desmosomes. © 2010 British Association of Dermatologists. Source

Dyment D.A.,Childrens Hospital of Eastern Ontario | Smith A.C.,University of Ottawa | Alcantara D.,University of Sussex | Schwartzentruber J.A.,McGill University | And 16 more authors.
American Journal of Human Genetics

SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906-1907insC (p.Asn636Thrfs18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906-1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway. © 2013 The American Society of Human Genetics. Source

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