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Colorectal carcinoma (CRC) is the third most common cancer worldwide. Hereditary factors are important in 15%-35% of affected patients. This review provides an update on the genetic basis of inherited predisposition to CRC. Currently known genetic factors include a group of highly penetrant mutant genes associated with rare mendelian cancer syndromes and a group of common low-penetrance alleles that have been identified through genetic association studies. Additional mechanisms, which may underlie a predisposition to CRC, will be outlined, for example, variants in intermediate penetrance alleles. Recent findings, including mutations in POLE, POLD1 and NTHL1, will be highlighted, and we identify gaps in present knowledge and consider how these may be addressed through current and emerging genomic approaches. It is expected that identification of the missing heritable component of CRC will be resolved through evermore comprehensive cataloguing and phenotypic annotation of CRC-associated variants identified through sequencing approaches. This will have important clinical implications, particularly in areas such as risk stratification, public health and CRC prevention.

Mutations affecting over 2000 of the 20 000 or so genes in the human genome have been linked so far to specific inherited diseases, most of which are rare and have been poorly understood. Many of the genes involved encode components of intracellular signalling pathways that regulate processes such as the growth, proliferation, differentiation and survival or programmed death of cells during development and the maintenance of tissues and organs. Mutations that change the function of genes encoding signalling proteins thereby cause disorders ranging from birth defects to cancer. For Mendelian disorders, the essentially causal relationship between mutation and disease may present direct opportunities to therapeutically manipulate intracellular signalling. Here, we review recent examples of the use of small-molecule drugs to target components of signalling networks in single-gene disorders. We also consider the limitations of these "molecularly targeted" approaches and the difficulties in their clinical development as therapies for rare genetic diseases.

Background Tuberous sclerosis complex is a multisystem genetic disease, caused by mutation in the TSC1 or TSC2 genes, associated with many features, including intellectual disability (ID). We examined psychometric profiles of patients with TSC1 or TSC2 mutations and tested whether different mutation types were associated with different degrees of intellectual ability. Methods One hundred subjects with known TSC1 / TSC2 mutations were assessed using a range of IQ or developmental quotient (DQ) measures. Effects of mutations on TSC1/TSC2 proteins were inferred from sequence data and published biochemical studies. Results Most individuals with TSC1 mutations fell on a normal distribution identical to the general population, with ∼10% showing profound ID. Of individuals with TSC2 mutations, 34% showed profound ID, and the remainder a pattern of IQ/DQ more variable and shifted to the left than in TSC1 or the general population. Truncating TSC1 mutations were all predicted to be subject to nonsense-mediated mRNA decay. Mutations predicted to result in unstable protein were associated with less severe effects on IQ/DQ. There was a statistically significant negative correlation between length of predicted aberrant C-terminal tails arising from frameshift mutations in TSC1 and IQ/DQ; for TSC2 a positive but not statistically significant correlation was observed. Conclusion We propose a model where (i) IQ/DQ correlates inversely with predicted levels and/or deleterious biochemical effects of mutant TSC1 or TSC2 protein, and (ii) longer aberrant C-terminal tails arising from frameshift mutations are more detrimental for TSC1 and less for TSC2. Predictions of the model require replication and biochemical testing.

MECP2 mutations are identifiable in approximately 80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis, but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using multiplex ligation dependent probe amplification or quantitative fluorescent PCR. Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193; p0.0001). Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.

Beckwith-Wiedemann syndrome (BWS) is a model imprinting disorder resulting from mutations or epimutations affecting imprinted genes on chromosome 11p15.5.1 The classical clinical features of BWS are macroglossia, pre- and/or postnatal overgrowth, and anterior abdominal wall defects (umbilical hernia or exomphalos). Additional more variable features include hemihypertrophy, neonatal hypoglycaemia, facial naevus flammeus, ear pits and creases, renal anomalies, and an increased risk of embryonal tumours.2 Most cases of BWS are sporadic and ∼20% of these have uniparental disomy (paternal isodisomy) for a variable region of chromosome 11 which always includes the 11p15.5 imprinted gene cluster.3–5 Up to 60% of sporadic BWS patients have epigenetic changes at differentially methylated regions within 11p15.5 that are associated with alterations in the imprinting or expression of paternally expressed genes, such as IGF2 and KCNQ1OT , or maternally expressed genes, such as H19 and CDKN1C .1 Thus, 5–10% have epigenetic alterations at the IGF2 / H19 loci (the maternal H19 and IGF2 alleles display paternal allele methylation and expression patterns with biallelic IGF2 expression and silencing of H19 expression),6 and 40–50% have loss of maternal allele methylation at a differentially methylated region (KvDMR1) within an intron of KCNQ1 . KvDMR1 loss of methylation is associated with biallelic expression of KCNQ1OT .7–9 The epigenetic alterations at H19 / IGF2 or KvDMR1 are thought to result from defects at two putative imprinting control centres (BWSIC1 and BWSIC2, respectively).1 The precise nature of the putative BWSIC2 is unknown and therefore the origin of these putative BWSIC2 defects is unknown. Weksberg et al 10 showed a clear association between monozygotic twinning and BWS with KvDMR1 loss of methylation and suggested two possible explanations: (1) that discordance for BWS in monozygotic twins is caused by unequal splitting of the inner cell mass …

Previous linkage studies in tuberous sclerosis have implicated three disease determining loci at 9q, 11q, and 12q. We have collated phenotypic and genotypic data on 1622 members of 128 families with tuberous sclerosis in order to evaluate simultaneously the evidence for these putative loci. Affection status in the family members has been reassessed using uniform diagnostic criteria and genotypic data extensively checked before analysis under alternative models of locus heterogeneity. One tuberous sclerosis determining locus, accounting for approximately 50% of the families studied, has been found to map in the region of D9S10 on 9q34 but no evidence has been found to support the existence of major loci on 11q or 12q. A locus, or loci, elsewhere in the genome is likely to account for tuberous sclerosis in most non-chromosome 9 linked families.

Background Women with a germline mutation in one of the MMR genes MLH1 , MSH2 or MSH6 reportedly have 4–12% lifetime risk of ovarian cancer, but there is limited knowledge on survival. Prophylactic bilateral salpingo-oophorectomy (PBSO) has been suggested for preventing this condition. Aim The purpose of this retrospective multicentre study was to describe survival in carriers of pathogenic mutations in one of the MMR genes, and who had contracted ovarian cancer. Methods Women who had ovarian cancer, and who tested positive for or were obligate carriers of an MMR mutation, were included from 11 European centres for hereditary cancer. Most women had not attended for gynaecological screening. Crude and disease specific survival was calculated by the Kaplan–Meier algorithm. Results Among the 144 women included, 81.5% had FIGO stage 1 or 2 at diagnosis. 10 year ovarian cancer specific survival independent of staging was 80.6%, compared to less than 40% that is reported both in population based series and in BRCA mutation carriers. Disease specific 30 year survival for ovarian cancer was 71.5%, and for all hereditary non-polyposis colon cancer (HNPCC)/Lynch syndrome related cancers including ovarian cancer it was 47.3%. Conclusions In the series examined, infiltrating ovarian cancer in Lynch syndrome had a better prognosis than infiltrating ovarian cancer in BRCA1/2 mutation carriers or in the general population. Lifetime risk of ovarian cancer of about 10% and a risk of dying of ovarian cancer of 20% gave a lifetime risk of dying of ovarian cancer of about 2% in female MMR mutation carriers.

A locus for Peutz-Jeghers syndrome (PJS) was recently mapped to chromosome 19p13.3. Each of 12 families studied was compatible with linkage to the marker D19S886. We have analysed 20 further families and found that the majority of these are consistent with a PJS gene on 19p13.3. Three families were, however, unlinked to 19p13.3 and none of the available PJS polyps from these families showed allele loss at D19S886. There were no obvious clinicopathological or ethnic differences between the 19p13.3 linked and unlinked families. There appears, therefore, to be a major PJS locus on chromosome 19p13.3 and the possibility exists of a minor locus (or loci) elsewhere.

Introduction: Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that is usually associated with mutations in the MECP2 gene. The most common mutations in the gene are p.R168X and p.T158M. The influence of X-chromosome inactivation (XCI) on clinical severity in patients with RTT with these mutations was investigated, taking into account the extent and direction of skewing. Methods: Female patients and their parents were recruited from the UK and Australia. Clinical severity was measured by the Pineda Severity and Kerr profile scores. The degree of XCI and its direction relative to the X chromosome parent of origin were measured in DNA prepared from peripheral blood leucocytes, and allele-specific polymerase chain reaction was used to determine the parental origin of mutation. Combining these, the percentage of cells expected to express the mutant allele was calculated. Results: Linear regression analysis was undertaken for fully informative cases with p.R168X (n = 23) and p.T158M (n = 20) mutations. A statistically significant increase in clinical severity with increase in the proportion of active mutated allele was shown for both the p.R168X and p.T158M mutations. Conclusions: XCI may vary in neurological and haematological tissues. However, these data are the first to show a relationship between the degree and direction of XCI in leucocytes and clinical severity in RTT, although the clinical utility of this in giving a prognosis for individual patients is unclear.

Objective: To determine the frequency of mutations in CDKL5 in both male and female patients with infantile spasms or early onset epilepsy of unknown cause, and to consider whether the breadth of the reported phenotype would be extended by studying a different patient group. Methods: Two groups of patients were investigated for CDKL5 mutations. Group 1 comprised 73 patients (57 female, 16 male) referred to Cardiff for CDKL5 analysis, of whom 49 (42 female, 7 male) had epileptic seizure onset in the first six months of life. Group 2 comprised 26 patients (11 female, 15 male) with infantile spasms previously recruited to a clinical trial, the UK Infantile Spasms Study. Where a likely pathogenic mutation was identified, further clinical data were reviewed. Results: Seven likely pathogenic mutations were found among female patients from group 1 with epileptic seizure onset in the first six months of life, accounting for seven of the 42 in this group (17%). No mutations other than the already published mutation were found in female patients from group 2, or in any male patient from either study group. All patients with mutations had early signs of developmental delay and most had made little developmental progress. Further clinical information was available for six patients: autistic features and tactile hypersensitivity were common but only one had suggestive Rett-like features. All had a severe epileptic seizure disorder, all but one of whom had myoclonic jerks. The EEG showed focal or generalised changes and in those with infantile spasms, hypsarrhythmia. Slow frequencies were seen frequently with a frontal or fronto-temporal predominance and high amplitudes. Conclusions: The spectrum of the epileptic seizure disorder, and associated EEG changes, in those with CDKL5 mutations is broader than previously reported. CDKL5 mutations are a significant cause of infantile spasms and early epileptic seizures in female patients, and of a later intractable seizure disorder, irrespective of whether they have suspected Rett syndrome. Analysis should be considered in these patients in the clinical setting.

Multifocal renal cell carcinomas (RCCs), together with angiomyolipomas (AMLs) and renal cysts, were identified in early adult life in two sisters with tuberous sclerosis (TSC). They were members of a multigenerational tuberous sclerosis family showing strong evidence for a mutant TSC causing gene on chromosome 9 (TSC1). Previous reports of multifocal RCC in young patients with TSC suggest that constitutional mutations at the TSC loci may predispose to RCC. In the rat a germline mutation affecting the TSC2 gene is associated with transmission of multifocal RCC as an autosomal dominant trait. However, the cases reported here are the first to suggest a similar role for the TSC1 gene in renal cell carcinogenesis.

Analysis of a large tuberous sclerosis pedigree confirmed linkage to a locus on the long arm of chromosome 9, with recombination events placing the disease gene distal to gelsolin and proximal to dopamine beta-hydroxylase.

Complete ascertainment of tuberous sclerosis was attempted in the west of Scotland (population 2,763,000). A total of 101 patients was identified, giving an overall minimum prevalence of 1 in 27,000, but for children under 10 years of age the minimum prevalence was 1 in 12,000. Both parents of 84 of the ascertained cases were assessed for signs of tuberous sclerosis. In 51 pairs of parents no evidence of the condition was seen, indicating that up to 60% of the cases were new mutations. The mutation rate was estimated at 2.5 X 10(-5) mutations per gene per generation. Analysis of parental ages for the new mutations did not show a significant age effect. Thirty-five patients occurred in 13 families containing other affected subjects. The pattern of inheritance was consistent with an autosomal dominant trait in these families. In one sibship, non-penetrance or gonadal mosaicism resulted in affected sibs with normal parents. Of two further sibships where non-penetrance was suspected, one was shown to represent a single new mutation in monozygotic twins and the other to involve non-paternity.