Causative Gene Localization For Two Kinds Of Monogenic Disorders And Prenatal Diagnosis

BackgroundSingle-gene disorder (monogenic disorder) is a kind of disease caused by single (allelic) gene mutations. The transmission mode is consistent with Mendelian law, it is also known as Mendelian genetic disease. According to the transmission modes of monogenic disease, it can be divided into following types:autosomal dominant inheritance, autosomal recessive inheritance and sex-linked inheritance. Currently, there are more than 6600 kinds of monogenic diseases, and the annual growth is to achieve 10～50 species. Thus, single-gene disorders threaten the human health greatly. Primary retinitis pigmentosa (RP) and spinocerebellar ataxia (SCA) are two kinds of single-gene disorders and the pathogenic mechanism have not yet clear.Primary retinitis pigmentosa (RP, OMIM 268000) is a group of clinically and genetically heterogeneous retinal degenerations. RP is characterized by pathological changes of night blindness, atrophy and pigment degenerations of the retina and retinal pigment epithelium, progressive narrowing or loss of the visual field and/or central visual acuity, attenuation of the retinal vasculature and pathological changes to the papilla of the optic nerve. The modes of inheritance for primary RP include autosomal dominant retinitis pigmentosa (adRP), autosomal recessive retinitis pigmentosa (arRP) and X-linked retinitis pigmentosa (xLRP). Mitochondrial and digenic inheritance are also well documented. Spinocerebellar ataxia is a group of autosomal dominant ataxia-based genetic degeneration of the nervous system. The pathological changes of spinocerebellar ataxias mainly include the degeneration of the cerebellum, spinal cord and brainstem. Nowadays, there haven’t had effective treatments for these kinds of single-gene disorders. Due to the high clinically and genetically heterogeneity, it is one of the most important roles to understand the fundamentals of molecular genetics which are beneficial for prenatal diagnosis, disease prevention and control.ObjectiveOur objective are to identify the causative genetic locus in a Chinese autosomal dominant retinitis pigmentosa (adRP) family H11, which contained seven affected members in three generations and to investigate the genotype of a three-generation Chinese Han pedigree (Yang-1018)with an autosomal dominant spinocerebellar ataxia which is for clinical diagnosis and genetic counseling.MethodsH11 family:After clinical diagnosis and exclusion of all mapped genes and loci, the SLINK program was used to simulate the maximum logarithm of the likelihood ratio (LOD) score for a linkage study in this small family. A genome-wide scan was performed using microsatellite markers at 10 cM intervals. Two-point and multipoint LOD scores were calculated, and haplotypes were constructed.Yang-1018 family:Direct mutation test and linkage analysis were performed. SCA1-8, SCA10-14, SCA17, SCA27 and dentatorubral-pallidoluysian atrophy (DRPLA) were excluded by mutation analysis while SCA 15/16/29, SCA18, SCA19/22, SCA20, SCA21, SCA23, SCA25, SCA26, SCA28 and SCA30 were excluded by linkage analysis.ResultsH11 family:The Hll family clinical presentation included an early onset of night blindness, a progressive loss of the peripheral visual field, typical RP fundus changes and a cataract complication. The maximum two-point LOD score of 2.54 (θ=0) was found at markers D1S2739, D1S457, D1S187, D1S189 and D1S305, and multipoint linkage analysis yielded a maximum LOD score of 2.54 for marker D1S187. These LOD scores were the closest to the maximum simulated LOD score. Haplotype analysis revealed that this form of adRP was linked to a 38.25 cM region that spanned 50 Mb on chromosome Ip22.1-q12.Yang-1018 family:We excluded all of the previously identified SCA-associated genes and loci. Interestingly, one patient (Ⅲ-13) had a novel mutation of the Purkinje cell atrophy associated protein-1 gene (PLEKHG4), and another patient (Ⅱ-7) had a novel mutation of theβ-Ⅲspectrin gene (SPTBN2) (Genbank accession numbers FJ905766 and FJ811850, respectively). However, these mutations were not common in other patients. In addition, open reading frame (ORF) on protein sequences were not changed.ConclusionsH11 family:Although this locus overlaps ABCA4 and RP32, that gene and locus, respectively, are inherited in an autosomal recessive mode rather than the autosomal dominant mode of inheritance mode found in the H11 family. Thus, the responsible mutation for the H11 family is unlikely to be the same as those for ABCA4 and RP32. The identification of this novel locus further confirms the wide heterogeneity of adRP.Yang-1018 family:Mutations of the PLEKHG4 gene and the SPTBN2 gene are not the causes of SCAs in this family. This autosomal dominant cerebellar ataxia family is likely a new genotype of SCAs. The causative locus and genes should rely on the completion of genome-wide scanning and gene function research.