Mutations in splicing factor genes are a major cause of autosomal dominant retinitis pigmentosa in Belgian families

Purpose : Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition. Methods : Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations. Results : Molecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5-30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%). Conclusions : Overall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular spectrum of PRPH2, PRPF8, RHO, RP1, SNRNP200, and TOPORS-associated adRP by the identification of 17 novel mutations

Successful hematopoietic stem cell transplantation for myelofibrosis in an adult with warts-hypogammaglobulinemia-immunodeficiency-myelokathexis syndrome

publisher: Elsevier articletitle: Successful hematopoietic stem cell transplantation for myelofibrosis in an adult with warts-hypogammaglobulinemia-immunodeficiency-myelokathexis syndrome journaltitle: Journal of Allergy and Clinical Immunology articlelink: http://dx.doi.org/10.1016/j.jaci.2016.04.057 content_type: article copyright: © 2016 American Academy of Allergy, Asthma & Immunologystatus: publishe

Human DOCK2 Deficiency: Report of a Novel Mutation and Evidence for Neutrophil Dysfunction

DOCK2 is a guanine-nucleotide-exchange factor for Rac proteins. Activated Rac serves various cellular functions including the reorganization of the actin cytoskeleton in lymphocytes and neutrophils and production of reactive oxygen species in neutrophils. Since 2015, six unrelated patients with combined immunodeficiency and early-onset severe viral infections caused by bi-allelic loss-of-function mutations in DOCK2 have been described. Until now, the function of phagocytes, specifically neutrophils, has not been assessed in human DOCK2 deficiency. Here, we describe a new kindred with four affected siblings harboring a homozygous splice-site mutation (c.2704-2 A > C) in DOCK2. The mutation results in alternative splicing and a complete loss of DOCK2 protein expression. The patients presented with leaky severe combined immunodeficiency or Omenn syndrome. The novel mutation affects EBV-B cell migration and results in NK cell dysfunction similar to previous observations. Moreover, both cytoskeletal rearrangement and reactive oxygen species production are partially impaired in DOCK2-deficient neutrophils

Mutations identified in the Belgian cohort.

<p>Mutations identified in the Belgian cohort.</p

Composite fundus photographs of 12 patients with mutations in <i>RHO</i>, <i>RP1</i>, <i>SNRNP200</i>, <i>PPRF8</i>, <i>PRPF31</i>, <i>TOPORS</i> and <i>NR2E3</i> leading to adRP.

<p>Overall, the phenotypes shown represent a range of adRP phenotypes varying from milder, classic, to end-stage RP. (A) Age 55 years (FAM_009), <i>RHO</i> mutation, c.1028G>A p.(Ser343Asn) (novel). A classic RP phenotype, including good macular preservation, attenuated retinal vasculature, outer retinal atrophy and predominantly spicular intraretinal pigment migration in the midperiphery. (B) Age 54 years (FAM_010), <i>RHO</i> mutation, c.1028G>A p.(Ser343Asn) (novel). Milder phenotype compared to A. Diffuse outer retinal atrophy in the periphery with good macular preservation. Notice the absence of intraretinal pigment migration. (C) Age 55 years (FAM_002), <i>RHO</i> mutation, c.265G>C p.(Gly89Arg) (novel). End-stage RP with macular atrophy, attenuated retinal vasculature and diffuse intraretinal pigment migration in the midperiphery. (D) Age 53 years (FAM_043), recurrent <i>NR2E3</i> mutation, c.166G>A p.(Gly56Arg). Outer retinal atrophy with mild intraretinal pigment migration in the periphery and perifoveal outer retinal atrophy. (E) Age 51 years (FAM_017), <i>RP1</i> mutation, c.2245_2248delinsTGAG p.(Leu749*) (novel). A classic RP phenotype, similar to the description of panel A. (F) Age 72 years (FAM_016), <i>RP1</i> mutation, c.2200del p.(Ser734Valfs*4) (novel). End-stage RP with complete outer retinal atrophy and intraretinal pigment migration including periphery and macula. (G) Age 72 years (FAM_019), <i>RP1</i> mutation, c.2597del p.(Leu866*) (novel). Typical yellowish hue due to outer retinal atrophy with intraretinal pigment migration in the periphery and macular preservation. (H) Age 30 years (FAM_022), <i>SNRNP200</i> mutation, c.1981G>T p.(Val661Leu) (novel). Outer retinal atrophy with spicular intraretinal pigment migration, most pronounced in the retinal midperiphery. (I) Age 38 years (FAM_025), <i>PRPF8</i> mutation, c.6840C>A p.(Asn2280Lys) (novel). Outer retinal atrophy with intraretinal pigment migration of the spicular type in the midperiphery and a good macular preservation. (J) Age 50 years (FAM_028), <i>PRPF8</i> mutation, c.6964G>T p.(Glu2322*) (novel). Mild outer retinal atrophy in the periphery with macular preservation, normal retinal vasculature and a normal optic disc. (K) 53 years (FAM_035), <i>PRPF31</i> mutation, c.541G>T p.(Glu181*). Outer retinal atrophy with macular preservation. (L) 51 years (FAM_048), <i>TOPORS</i> mutation, c.2556_2557del p.(Glu852Aspfs*20) (novel). Pigment epithelium alterations with white dots in the retinal periphery. Notice absence of intraretinal pigment migration and presence of perifoveal atrophy.</p

Schematic representation of novel mutations and prevalence of causal mutations in adRP genes.

<p>(A-D): Schematic representation of the novel mutations identified in this study. (A) <i>RP1</i> gene. The five mutations are located within the mutational hotspot (nucleotides 1490–3216), indicated with a black horizontal line. E = exon. Grey rectangles are coding regions and orange rectangles are 5’ untranslated region (5’ UTR) and 3’ UTR. (B) RP1 protein. Both truncating mutations identified in this study belong to Class II mutations (amino acids 500–1053), indicated with a black line. The <i>Drosophila melanogaster</i> (BIF) domain (amino acids 486–635) is depicted as a blue rectangle. aa = amino acid. (C) SNRNP200 protein. The two novel mutations identified in this study are both located within the first DExD/H box helicase-like domain (amino acids 477–690). Both the first and the second (amino acids 1324–1528) DExD/H box helicase domains are represented as blue rectangles. Both Sec63-like domains (amino acids 981–1286 and 1812–2124) are indicated as golden rectangles. aa = amino acids. (D) PRPF8 protein. The novel mutation identified here is located within the highly conserved region C-terminal to the Jab1/MPN domain (amino acids 2099–2233), depicted as a blue rectangle. aa = amino acid. (E) Prevalence of causative mutations in adRP genes in a Belgian adRP cohort. The ‘unknown’ part may include new disease genes and mutation mechanisms as well as known disease genes not screened in the course of this study.</p