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We present a case of a fetus with hyperechogenic bowel, in which the L548Q mutation was detected in the mother of Japanese origin and the deltaF508 mutation in the father of Caucasian origin. The fetus proved to be compound heterozygous. Research into cystic fibrosis transmembrane conductance regulator (CFTR) mutations in this case was triggered by the fact that the fetus had a characteristic hyperechogenic bowel image with normal karyotype and no indications of intrauterine infections. Hyperechogenic bowel is highly indicative of a CFTR gene mutation. The incidence of cystic fibrosis (CF) in fetuses with mid-trimester hyperechogenic bowel is 5%, but once the most frequent mutations have been accounted for, rarer mutations must be investigated.

Editor—Cystic fibrosis (CF, MIM 219700) is a common, severe, autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator ( CFTR ) gene cloned in 1989.1-3The disease, characterised by chronic lung disease which is the main cause of morbidity and mortality, pancreatic dysfunction, raised electrolyte levels in sweat, and male infertility, is caused by altered chloride (Cl−) secretion across the apical membrane of epithelial cells.4 There is, however, substantial variability in the clinical manifestations affecting the various organs.4 5 One single mutation, F508del, generally associated with severe disease, accounts for about 70% of CF chromosomes world wide, although with a heterogeneous geographical distribution.5 Patients homozygous for the F508del mutation have the classical severe form of the disease which includes chronic mucous obstruction of the lung and conducting airways, followed by recurrent infections mostly by Pseudomonas aeruginosa (Pa) and Staphylococcus aureus (Sa), exocrine pancreatic insufficiency (PI), resulting in failure to gain weight and height, and raised levels of Cl−, sodium, and potassium in exocrine sweat.5 However, almost 1000 genetic alterations have been detected in the CFTR gene ( CFTR Mutation Database), most presumed to be disease causing mutations. About half of these are amino acid substitutions (missense mutations) and about 20% are splicing mutations. The remainder are nonsense, frameshift (including small deletions and insertions), and a small proportion of promoter mutations. The relationship between genotype, that is, the mutations in the CFTR gene, and the clinical phenotype of CF patients has been difficult to establish, in particular for lung disease. It was previously shown that the 3272-26A>G mutation leads to the creation of an alternative acceptor splice site competing with the normal one during RNA processing and resulting in the occurrence of an alternatively spliced mRNA with 25 extra nucleotides from …

We studied the NF1 gene in 93 unrelated patients with neurofibromatosis type1, focusing the analysis on four exons that contain the highest number of possible mutations occurring at CpG sites. We used denaturing gradient gel electrophoresis to analyse exons 16, 28, 29 and 49, which contain 45 (25%) of the 183 possible mutations that could occur at the 120 CpG dinucleotides of the coding sequence. Six different mutations were identified, five of which are novel: two truncating mutations, W1810X and 5448insG, located in exon29; two splice defects leading to exon29 skipping, 5206-2A>G and 5546G>A; and one missense mutation, L844F, located in exon16. The already described R1748X mutation located in exon29 was found in two unrelated patients. The 5546G>A and R1748X mutations are located at CpG sites, whereas the W1810X involves a CpNpG site. Four novel polymorphisms, which may be helpful for family studies, were also identified. Overall, all but one mutations were found in exon29, a result which suggests that all the CpG sites of the NF1 coding sequence do not have the same mutability, and that exon29, the most CpG-rich exon, contains mutational hotspots associated with NF1.

Editor—Cystic fibrosis (CF) is an autosomal recessive disorder affecting 1/2500 live births in northern European populations1 and is caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene.2 Data accumulated over the past 10 years have produced a remarkable repository of mutations and polymorphisms of the CFTR gene.3 However, the clinical consequences of many rare mutations are still poorly understood and functional studies are not routinely available. Because of the mutational heterogeneity and the rarity of many mutations, most clinical DNA laboratories offer tests that aim to detect 85-90% of CF alleles, and the systematic, cumbersome analysis of the rest of the gene is performed in selected cases only. With the increasing demand for prenatal screening of pregnancies from the general population, an increasing number of CF patients are diagnosed in utero in the absence of a family history of CF, either after preconceptional genetic screening of the parents, or after a routine fetal ultrasound showed a CF associated finding, for example, fetal bowel hyperechogenicity (FBH). In such instances, reliable genotype-phenotype correlations are required for appropriate counselling. FBH is defined as an echogenicity of a fetal bowel loop similar to or greater than the fetal iliac crest4 and is found in 0.5-1% of all second trimester pregnancies.5 Whether hyperechogenicity in FBH originates from the bowel wall or from intraluminal content remains a matter of debate.4 It is a non-specific sign that is associated with CF in some cases.1 4 6 In a study of 209 pregnancies with FBH, 68% had a subsequent normal outcome and 3.3% had CF, the other cases corresponding to chromosomal abnormalities (5%), gastrointestinal malformations (8%), fetal infection (4%), or unexplained fetal death (13%).5 7 Before 18 weeks' gestation, the assay of gastrointestinal enzymes in …