Breast cancer,consanguinity, and lethal tumor genes: simulation of BRCA1/2 prevalence over 40 generations

Marriage between biological relatives is a social custom with a long history in many parts of the world. Today, hundreds of millions of individuals live in consanguineous families. The offspring of consanguineous parents are more likely to have the same two alleles (homozygosity) by descent. In consanguineous family with BRCA1/2 gene mutations, an offspring is more likely to be BRCA1/2 homozygous. The consequences of BRCA1/2 mutation homozygosity in humans are unknown. In knockout mice, BRCA1 or BRCA2 homozygotes die as embryos. Because tumor suppressor genes are conserved and less species-specific than other genes, human BRCA1/2 homozygotes are likely to be biologically non-viable and are unknown to exist. Among the conceptuses of consanguineous couples, there are excess deaths (abortions, stillbirths, perinatal and early-childhood deaths) as well as a decreased risk of breast cancer, especially in younger females. It has been suggested that, in part, the excess deaths are due to BRCA1/2 and other still undiscovered tumor gene homozygotes. To examine the consequences of the long-term practice of consanguineous marriage on the prevalence of lethal cancer genes, we simulated, by computer, the mating of non-consanguineous and consanguineous populations over 40 generations. The program was developed in Basic for a Macintosh computer. The input comprised the rates of consanguineous marriage types and the output parameter was the rate of heterozygotes (carriers) in each generation. The combined prevalence of BRCA1/2 mutation of 1% was used as a starting reference point. Absence of spontaneous mutations and gene flow were assumed. In a randomly mating population, the BRCA1/2 carrier rate decreases on average 0.0035% every 25 years. In a highly consanguineous population, the carrier rate decreases on average 0.022% every 25 years, or six times faster than in a non-consanguineous population. There is a worldwide trend of decreasing breast cancer incidence with an increasing consanguinity rate. In conclusion, the BRCA1/2 and possibly other undiscovered tumor gene carrier rates are significantly lower in consanguineous than in non-consanguineous populations. Gene frequency in a population depends on the rate of inbreeding and length of consanguineous practices. A drift phenomenon may exert a major effect on the carrier rate. Consanguinity may explain part of the worldwide variation of breast cancer incidence.     

The genetic basis of inherited primary nocturnal enuresis: A UAE study

OBJECTIVE: Nocturnal enuresis is defined as involuntary emptying of the bladder in the absence of an organic cause in a child aged 5 years or older. Primary nocturnal enuresis (PNE) is the term used if the child has never been dry. Of several factors implicated in the etiology of PNE, genetic factors appear to be the strongest. In about 75% of affected children, there is a strong family history. The purpose of this study was to examine the genetic basis of nocturnal enuresis among children in the United Arab Emirates (UAE). METHODS: Chromosomes 12 and 13 were genotyped in all family members of 10 affected children in four large families. Linkage to earlier reported microsatellite markers on these two chromosomes was examined. RESULTS: In the four families examined, we did not find evidence for linkage to the two loci reported previously. CONCLUSIONS: Among UAE children examined, no linkage was found between PNE and the loci reported previously on chromosomes 12 and 13, indicating further genetic heterogeneity in PNE.     

A recessive truncating variant in thrombospondin‐1 domain containing protein 1 gene THSD1 is the underlying cause of nonimmune hydrops fetalis,congenital cardiac defects,and haemangiomas in four patients from a consanguineous family

Non‐immune hydrops fetalis (NIHF) is the abnormal accumulation of serous fluid in more than two fetal or neonatal interstitial spaces due to nonimmune causes. It is a serious condition that requires extensive medical care as it indicates severe fetal compromise. We clinically evaluated four patients from two branches of a highly consanguineous family from the UAE with NIHF using whole exome sequencing and in silico analysis. Fetal onset pleural and peritoneal effusions were detected in all four patients and were born with moderate to severe hydrops fetalis that resolved with age. Follow up showed relatively normal growth and development apart from mild ascites and haemangiomas in all affected children, recurrent hydrocele in all affected males, intestinal malabsorption in two patients, dysmorphic features in two patients, and congenital cardiac defects in three out of four patients. Molecular testing identified a homozygous eight nucleotide deletion in THSD1 gene (NM_199263:c.1163_1170delGGCCAGCC, p.Arg388Glnfs*66) as the underlying cause of this phenotype in the affected children. The novel variant cosegregates with the described phenotype in an autosomal recessive mode of inheritance and is predicted to be pathogenic as it leads to a truncated protein that lost important structural and functional domains. Thrombospondin‐1 domain containing protein 1 gene THSD1 has been recently associated with of NIHF and embryonic lethality. Here, we report the novel truncating THSD1 variant, and describe new clinical features that have not been reported previously thus expanding the phenotype associate with loss‐of‐function mutations in THSD1 causing NIHF.     

Diagnostic Exome Sequencing to Elucidate the Genetic Basis of Likely Recessive Disorders in Consanguineous Families

Rare, atypical, and undiagnosed autosomal‐recessive disorders frequently occur in the offspring of consanguineous couples. Current routine diagnostic genetic tests fail to establish a diagnosis in many cases. We employed exome sequencing to identify the underlying molecular defects in patients with unresolved but putatively autosomal‐recessive disorders in consanguineous families and postulated that the pathogenic variants would reside within homozygous regions. Fifty consanguineous families participated in the study, with a wide spectrum of clinical phenotypes suggestive of autosomal‐recessive inheritance, but with no definitive molecular diagnosis. DNA samples from the patient(s), unaffected sibling(s), and the parents were genotyped with a 720K SNP array. Exome sequencing and array CGH (comparative genomic hybridization) were then performed on one affected individual per family. High‐confidence pathogenic variants were found in homozygosity in known disease‐causing genes in 18 families (36%) (one by array CGH and 17 by exome sequencing), accounting for the clinical phenotype in whole or in part. In the remainder of the families, no causative variant in a known pathogenic gene was identified. Our study shows that exome sequencing, in addition to being a powerful diagnostic tool, promises to rapidly expand our knowledge of rare genetic Mendelian disorders and can be used to establish more detailed causative links between mutant genotypes and clinical phenotypes.     

Transmission and Cross-Mating of High-Level Resistance Plasmodium falciparum Dihydrofolate Reductase Haplotypes in The Gambia

A high-level pyrimethamine resistance Plasmodium falciparum lineage with triple dihydrofolate reductase (dhfr) mutations prevails across Africa. However, additional minority lineages were seen. We examined transmission success of mutant dhfr haplotypes among 22 children in The Gambia and 60 infected Anopheles gambiae mosquitoes fed on their blood. Additional polymorphic genes of the gametocyte-specific protein (pfg377) and merozoite surface protein-1 (MSP-1) were examined. Similarities were seen between pfg377 and MSP-1 alleles in children and mosquitoes and evidence of cross-mating between different parasite genotypes was seen in some infected mosquitoes, reflecting high transmission success of existing clones. With regard to dhfr, 16 haplotypes were seen among the children: 2 carried double mutations and 14 carried triple mutations. However, only nine haplotypes, all with triple mutations, were detected among mosquitoes. A single triple-mutant dhfr haplotype, similar to that in other countries in Africa, predominated among children (42%) and mosquitoes (60%), supporting the hypothesis of migration of this haplotype across Africa. However, evidence of cross-mating between the above haplotypes signifies the role of local evolution.     

Defective membrane expression of the Na+-HCO3? cotransporter NBCe1 is associated with familial migraine

Homozygous mutations in SLC4A4, encoding the electrogenic Na⁺-HCO₃⁻ cotransporter NBCe1, have been known to cause proximal renal tubular acidosis (pRTA) and ocular abnormalities. In this study, we report two sisters with pRTA, ocular abnormalities, and hemiplegic migraine. Genetic analysis ruled out pathological mutations in the known genes for familial hemiplegic migraine, but identified a homozygous 65-bp deletion (Δ65bp) in the C terminus of NBCe1, corresponding to the codon change S982NfsX4. Several heterozygous members of this family also presented glaucoma and migraine with or without aura. Despite the normal electrogenic activity in Xenopus oocytes, the Δ65bp mutant showed almost no transport activity due to a predominant cytosolic retention in mammalian cells. Furthermore, coexpression experiments uncovered a dominant negative effect of the mutant through hetero-oligomer formation with wild-type NBCe1. Among other pRTA pedigrees with different NBCe1 mutations, we identified four additional homozygous patients with migraine. The immunohistological and functional analyses of these mutants demonstrate that the near total loss of NBCe1 activity in astrocytes can cause migraine potentially through dysregulation of synaptic pH.