6 research outputs found
Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip
Variant filtration process illustrating the exome filtering scheme in two affected individuals. Panel 1: Genes containing rare variants (1% in 1000G/ExAC/in-house database; absent from dbSNP) and in accordance with an autosomal dominant inheritance with incomplete penetrance (shared between affected samples III:5 and IV:2). ACOT8, ADCK1, AGMO, ANGPT4, ANKS3, ATP2B4, BARHL1, C12orf44, C18orf56, CACTIN, CCM2L, CEACAM4, CRISPLD2, CTAGE7P, CTSA, CTSE, DAGLB, DAZAP2, DCTN4, DENND1B, EDEM1, EMG1, FAM154A, FAM19A2, GSK3A, HIPK1, HMCN2, HNRNPUL1, HSPG2, INCENP, INTS1, IRG1, KCNIP4, KHSRP, LEPREL2, LPPR3, MAN1C1, MICALCL, MREG, MUC5B, NAV1, NEURL2, NPR2, NUCKS1, PCSK5, PDS5A, PLCG2, POMT1, PPL, PRDM7, PRKAB1, SEZ6L, SLC6A12, SLC7A5, SLIT2, ZCCHC8, ZNF335, ZNF648, ZNF780A. (JPG 128 kb
A novel missense variant in the RASGRP2 gene in patients with moderate to severe bleeding disorder
Inherited platelet function disorder-18 (IPD-18) is a relatively new non-syndromic autosomal recessive bleeding disorder. It is characterized by deficient or dysfunctional CalDAG-GEFI protein. The distinctive feature of the disease is impaired platelet aggregation in response to multiple physiologic agonists. We here report a family with a platelet-type bleeding disorder and a novel mutation in the RASGRP2 gene. The overall bleeding score for the affected individuals was 15 and 12. Based on the initial diagnosis of Glanzmann thrombasthenia, targeted sequencing of integrin subunit alpha 2b and integrin subunit beta 3 encoding genes ITGA2B and ITGB3 were carried out in both affected members of a family. Sequence alignment failed to identify the disease-causing variant(s) in both genes. Therefore, whole exome sequencing in one affected individual was performed. Data analysis detected a novel homozygous missense variant (c.956C>T; p.Pro319Leu) in the exon 9 of the RASGRP2 gene. Five additional individuals of a family including both parents, an affected individual and two asymptomatic individuals were Sanger sequenced for the variant (c.956C>T). The variant segregates in the family in an autosomal recessive manner. Several in silico tools predicted the variant as pathogenic. Protein modeling studies suggest that the mutation (p.Pro319Leu) cause a conformational change in the loop structure of the RasGEF domain of the CalDAG-GEFI protein. Reported variants in the RasGEF domain impair expression and/or nucleotide exchange activity of CalDAG-GEFI protein and thus inhibit the activation of Rap1 protein required for platelet adhesion and hemostatic plug formation
Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip
Biallelic variants in HECT E3 paralogs, HECTD4 and UBE3C, encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome
Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified