Family-based Genetic Study Of Complex Diseases

This family-based genetic study includes familial hypercholesterolemia, mandibular prognathism and oculo-auriculo-vertebral spectrum. Familial hypercholesterolemia is a lipid metabolic genetic disease. Mandibular prognathism and oculo-auriculo-vertebral spectrum are oral-facial malformation.Familial hypercholesterolemia (FH) is an inherited disorder that increases the risk of premature coronary heart disease. Substantial genetic heterogeneity was suggested from studies of various populations. We tried to identify a novel susceptibility locus for FH in a Chinese pedigree. A SNP-based genome-wide linkage scan was performed with a Chinese FH pedigree. Two linkage loci, distinct form previously reported FH regions, were identified on chromosomes3q25.1-26.1(NPL=9.01) and21q22.3(NPL=8.95). Significantly increased joint LOD score (2.70) from the two separated single-locus LOD scores was detected with an interaction analysis under the assumption of two disease loci. It suggests that more than one locus is involved in this pedigree. Exon screening of two candidate genes ABCG1and LSS failed to identify a causative mutation. Conclusions/Significances:These results suggest new and complex genetic etiologies for the disease. Further study on the two candidate regions is warranted.Mandibular prognathism is a common dentofacial phenotype with a substantial genetic component; however, few susceptibility loci have been mapped. Ethnicity is a risk factor for mandibular prognathism, and a relatively high prevalence is observed in Asian populations. The hypothesis of this study suggested that a specific locus for mandibular prognathism exists in the Han Chinese population. So, the authors studied a Han Chinese pedigree in which mandibular prognathism was inherited (11affected,10unaffected) in an autosomal dominant pattern. A genomewide linkage scan was performed with the Illumina Linkage-12DNA Analysis Kit. Multipoint parametric and nonparametric linkage analyses were performed with MERLIN1.01. A susceptibility locus was identified on chromosome14q24.3-31.2, with a NPL score of11.341and a LOD score of2.032. Haplotype analysis refined the candidate locus to a10.62-cM interval (72.42to83.14cM;74.57to84.66Mb) between rs1468507and rs7141857. Within this interval, the candidate functional genes are TGFB3and LTBP2. In conclusion, we detected a suggestive linkage for mandibular prognathism in a Han Chinese pedigree, and this finding can be combined with previous studies to further understand the genetic basis of mandibular prognathism.Oculo-auriculo-vertebral spectrum (OAVS) is a common developmental disorder involving first and second pharyngeal arches. Although some family cases and such patients showing chromosomal aberrations suggest that OAVS have a genetic basis, no consistent genetic defects have been recorded at present time. Thus, we conducted genetic studies of a three-generation family with five OAVS patients to identify a causative variant for OAVS. Cytogenetic studies revealed those family members had a normal karyotype and no causative mutations were founded in SALL1and TCOF1, which known to be responsible for two other syndromes that have clinical overlapping with OAVS. Genotyping with commercially available BeadChips was performed on13individuals in the same family, showing no significant difference between the affected and normal members in terms of copy number variations (CNVs) in either number or size and no definitive causative CNV. A total of8,224informative autosomal SNPs that are evenly distributed throughout the genome were selected for both parametric and non-parametric linkage analysis. Significant negative LOD scores were obtained for the reported OAVS locus, providing further evidence for genetic heterogeneity of this complex disorder. The highest LOD score of1.60was noted on chromosome15q26.2-q26.3showing a potential linkage to this locus. The variable phenotypes of the affected members and the failure to identify a causative variant indicate that a complex etiology may be present even in a consanguineous family, which makes it more challenging to ascertain the cause of OAVS in further analysis.Another OAVS patient with multiple congenital anomalies, including hemifacial microsomia, asymmetric macrostomia, dysplastic mandible, multiple preauricular tags, atresia of the external auricular canal, and vertebral anomalies, which coincide with oculo-auriculo-vertebral spectrum. G-banding (w850band level) showed a normal46, XY karyotype. A genome-wide screen for copy number variations (CNVs) using single nucleotide polymorphism (SNP) arrays revealed a1Mb and a167kb deletion both on chromosome5q13.2, which were absent in the parents and in27controls. Sixteen genes were located in the deleted region, including BIR1C and OCLN, which are involved in apoptosis. Haploinsufficiency of these genes may be contributing to the phenotype in this patient. To our knowledge, there are no previous reports of this5q13.2deletion in a patient with OAVS.