Evolutionary evidence of the effect of rare variants on disease etiology

Gorlov IP, Gorlova OY, Frazier ML, Spitz MR, Amos CI. Evolutionary evidence of the effect of rare variants on disease etiology. The common disease/common variant hypothesis has been popular for describing the genetic architecture of common human diseases for several years. According to the originally stated hypothesis, one or a few common genetic variants with a large effect size control the risk of common diseases. A growing body of evidence, however, suggests that rare single‐nucleotide polymorphisms (SNPs), i.e. those with a minor allele frequency of less than 5%, are also an important component of the genetic architecture of common human diseases. In this study, we analyzed the relevance of rare SNPs to the risk of common diseases from an evolutionary perspective and found that rare SNPs are more likely than common SNPs to be functional and tend to have a stronger effect size than do common SNPs. This observation, and the fact that most of the SNPs in the human genome are rare, suggests that rare SNPs are a crucial element of the genetic architecture of common human diseases. We propose that the next generation of genomic studies should focus on analyzing rare SNPs. Further, targeting patients with a family history of the disease, an extreme phenotype, or early disease onset may facilitate the detection of risk‐associated rare SNPs.     

Double-strand breaks may initiate the inversion mutation causing the Hunter syndrome

We have previously shown that patients with the Hunter syndrome frequently have suffered from a recombination event between the IDS gene and its putative pseudogene, IDS-2, resulting in an inversion of the intervening DNA. The inversion, which might be the consequence of an intrachromosomal mispairing, is caused by homologous recombination between sequences located in intron 7 of the IDS gene and sequences located distal of exon 3 in IDS-2. In order to gain insight into the mechanisms causing the inversion, we have isolated both inversion junctions in six unrelated patients. DNA sequence analysis of the junctions showed that all recombinations have taken place within a 1 kb region where the sequence identity is >98%. An interesting finding was the identification of regions with alternating IDS gene and IDS-2 sequences present at one inversion junction, suggesting that the recombination event has been initiated by a double-strand break in intron 7 of the IDS gene. The results from this study suggest that homologous recombination in man could be explained by mechanisms similar to those described for Saccharomyces cerevisiae. The results also have practical implications for diagnosis of patients with the Hunter syndrome.      

Evidence that FGFR1 loss-of-function mutations may cause variable skeletal malformations in patients with Kallmann syndrome

PurposeLoss-of-function mutations in FGFR1 have been identified in approximately 10% of the Kallmann syndrome (KS) patients. Previous reports have focused mainly on olfactory, reproductive, and some other features such as cleft lip/palate and dental agenesis. Given the ubiquitous expression of FGFR1 during development, other abnormal phenotypes might, however, have been overlooked in these patients. Here, we demonstrate skeletal phenotypic characterization of patients presented with KS and FGFR1 mutations.Material and MethodsUsing the Sanger DNA sequencing technique a cohort of 29 KS patients was screened.ResultsHere, we report on 5 KS patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Three patients presented with skeletal abnormalities, i.e. spine (hemivertebra and butterfly vertebra) and limb (oligodactyly of the feet, fusion of the 4th and 5th metacarpal bones) malformations in two patients and one patient, respectively. The hand phenotype found in the patient cannot be thought of as a counter-type of the hand phenotype resulting from FGFR1 gain-of-function mutations. The skeletal anomalies identified in the 3 KS patients are close to those observed in Fgfr1 conditional knockout mice.ConclusionsThis study demonstrates that FGFR1 loss-of-function mutations can be associated with skeletal abnormalities also in humans. Further investigations in KS patients who carry FGFR1 mutations are needed to evaluate the prevalence of skeletal defects in this genetic form of KS. Conversely, the presence of bone malformations in a KS patient should direct the geneticist towards a search for mutations in FGFR1.