Genome-wide linkage analysis is a powerful prenatal diagnostic tool in families with unknown genetic defects

Abstract

Genome-wide linkage analysis is an established tool to map inherited diseases. To our knowledge it has not been used in prenatal diagnostics of any genetic disorder. We present a family with a severe recessive mental retardation syndrome, where the mother wished pregnancy termination to avoid delivering another affected child. By genome-wide scanning using the Affymetrix (Santa Clara, CA, USA) 10k chip we were able to establish the disease haplotype. Without knowing the exact genetic defect, we excluded the condition in the fetus. The woman finally gave birth to a healthy baby. We suggest that genome-wide linkage analysis - based on either SNP mapping or full-genome sequencing - is a very useful tool in prenatal diagnostics of diseases

Molecular Diagnostics of Ciliopathies and Insights Into Novel Developments in Diagnosing Rare Diseases

“…Defective genes associated with ADPKD include Polycystic Kidney Disease 1/2 (PKD1/2) , with PKD1 accounting for most ADPKD cases 14 ( Table 1 ). In comparison, ARPKD has been associated with mutations in Polycystic Kidney and Hepatic Disease 1 (PKHD1), with recent findings linking mutations in DAZ interacting protein 1-like (DZIP1L) with moderate ARPKD 17 . PKD1/2 and PKHD1 encode for Polycystin (PC)-1/2 and Fibrocystin respectively, proteins that localise to the cilium 1 , 4 , 5 , 14 , 15 .…”

“…Although linkage analysis helps identify markers that co-segregate with genes of interest, whilst also allowing for patient diagnosis confirmation in cases where mutation positions remain unknown 16 and it can be effectively used for neonatal/prenatal testing and can identify the carrier status of at-risk females 17 , it also has limitations. Linkage analysis has got the risk of recombination, which could result in incorrect carrier status and the rise of de novo mutations/mosaicisms 16 and it fails to provide details on the exact mutation type 17 , 18 , 19 . Another major difficulty associated with this technique is the requirement for multiple family members or generations for informative linkage analysis 16 , 19 , hence why direct mutation screening has become a more commonly practiced method of diagnosis.…”

Pairomics, the omics way to mate choice

“…Increasing heterozigosity with neutral markers It has been argued that the clinical management of sequence variations of unknown significance, including the consideration of abortion, makes genetic testing very difficult and ambivalent. [99][100][101] However, sequence variation is the general principle underlying genetic distance, and heterosis as a function of genetic distance has withstood the test of time. Therefore, it appears to be enough reason to use variable regions as markers in premarital genetic counseling for mate choice based on increasing heterosis in the offspring.…”