Maturity-onset diabetes of the young type 5 in a family with diabetes and mild kidney disease diagnosed by whole exome sequencing.

Exome sequencing is being increasingly used to identify disease-associated gene mutations. We used whole exome sequencing to determine the genetic basis of a syndrome of diabetes and renal disease affecting a mother and her son. We identified a mutation in the hepatocyte nuclear factor 1-b (HNF1B) gene that encoded a methionine to valine amino acid change (M160V) in the HNF1B protein. This leads us to the previously unappreciated diagnosis of maturity-onset diabetes of the young type 5 and provided a basis for genetic counselling of other family members.

Detection of repeat expansions in large next generation DNA and RNA sequencing data without alignment.

Bioinformatic methods for detecting short tandem repeat expansions in short-read sequencing have identified new repeat expansions in humans, but require alignment information to identify repetitive motif enrichment at genomic locations. We present superSTR, an ultrafast method that does not require alignment. superSTR is used to process whole-genome and whole-exome sequencing data, and perform the first STR analysis of the UK Biobank, efficiently screening and identifying known and potential disease-associated STRs in the exomes of 49,953 biobank participants. We demonstrate the first bioinformatic screening of RNA sequencing data to detect repeat expansions in humans and mouse models of ataxia and dystrophy.

Heterogeneity at the HLA-DRB1 allelic variation locus does not influence multiple sclerosis disease severity, brain atrophy or cognition.

BACKGROUND: HLA-DRB1*1501 (DR15) and other HLA class II alleles increase the risk of developing multiple sclerosis (MS). However, the contribution of genetic heterogeneity to the clinical course of MS remains controversial. We examined the influence of DR15 and other common DRB1 alleles (DRB1*01 (DR1), DRB1*03 (DR3) and DRB1*04 (DR4) on MS severity in a large, Australian, population-based cohort. METHODS: We studied the association between common HLA-DRB1 alleles and genotypes and age of onset as well as three clinical disease severity descriptors: Multiple Sclerosis Severity Score, progression index), and the interval between the first and second attack in 978 patients with relapsing remitting MS and secondary progressive MS. We assessed cognition using the Symbol Digit Modalities Test in 811 patients and brain atrophy using the linear magnetic resonance imaging marker, the intercaudate ratio, in 745 patients. RESULTS: Carrying DR15 significantly decreased the age of MS onset by 3.2 years in homozygotes and 1.3 years in heterozygotes. Carrying the HLA-DR15, -DR1, -DR3 or -DR4 alone or in combination did not affect clinical disease severity, cognition or cerebral atrophy. CONCLUSIONS: This study confirms that heterogeneity of HLA-DRB1 does not influence disease outcome in relapsing MS patients, with the exception of a younger age of onset in HLA-DR15 carriers.

Generating linkage mapping files from Affymetrix SNP chip data.

SUMMARY: LINKDATAGEN is a perl tool that generates linkage mapping input files for five different linkage mapping tools using data from all 11 HAPMAP Phase III populations. It provides rudimentary error checks and is easily amended for personal linkage mapping preferences. AVAILABILITY AND IMPLEMENTATION: LINKDATAGEN is available from http://bioinf.wehi.edu.au/software/linkdatagen/ with accompanying annotation files, reference manual and test dataset.

Variable hearing impairment in a DFNB2 family with a novel MYO7A missense mutation.

Myosin VIIA mutations have been associated with non-syndromic hearing loss (DFNB2; DFNA11) and Usher syndrome type 1B (USH1B). We report clinical and genetic analyses of a consanguineous Iranian family segregating autosomal recessive non-syndromic hearing loss (ARNSHL). The hearing impairment was mapped to the DFNB2 locus using Affymetrix 50K GeneChips; direct sequencing of the MYO7A gene was completed. The Iranian family (L-1419) was shown to segregate a novel homozygous missense mutation (c.1184G>A) that results in a p.R395H amino acid substitution in the motor domain of the myosin VIIA protein. As one affected family member had significantly less severe hearing loss, we used a candidate approach to search for a genetic modifier. This novel MYO7A mutation is the first reported to cause DFNB2 in the Iranian population and this DFNB2 family is the first to be associated with a potential modifier. The absence of vestibular and retinal defects, and less severe low frequency hearing loss, is consistent with the phenotype of a recently reported Pakistani DFNB2 family. Thus, we conclude this family has non-syndromic hearing loss (DFNB2) rather than USH1B, providing further evidence that these two diseases represent discrete disorders.

A new dominantly inherited pure cerebellar ataxia, SCA 30.

BACKGROUND: The spinocerebellar ataxias (SCAs) are clinically and genetically heterogeneous. Currently, 27 forms are known, with the causative gene identified in 16. Although the majority of dominant pedigrees worldwide have SCAs 1, 2, 3, 6 or 8, new SCAs continue to be delineated. We describe a new disorder: SCA 30. METHODS: An Australian family of Anglo-Celtic ethnicity manifested a relatively pure, slowly evolving ataxia. Six affected and four unaffected members were personally examined in a standardised fashion. MRI and nerve conduction studies were performed in two. An autosomal genome-wide linkage study was undertaken, and an in silico analysis of potential candidate genes in the linkage region was performed. RESULTS: The six affected members had a relatively pure, slowly evolving ataxia developing in mid to late life, with only minor pyramidal signs and no evidence of neuropathy. All had hypermetric saccades with normal vestibulo-ocular reflex gain. Only one displayed (slight) gaze-evoked nystagmus. MRI showed cerebellar atrophy with preservation of nodulus/uvula and brainstem. Linkage analysis excluded currently known SCAs and identified a logarithm (base 10) of odds score of 3.0 at chromosome 4q34.3-q35.1, distinct from all previously reported loci. In silico prioritisation identified the gene ODZ3 as the most likely contender. CONCLUSIONS: SCA 30 is a previously undescribed cause of (relatively) pure adult-onset autosomal dominant cerebellar ataxia. The responsible gene is yet to be determined, but ODZ3 is a plausible candidate.

Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians.

A recent genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC) identified a number of putative MS susceptibility genes. Here we have performed a replication study in 1134 Australian MS cases and 1265 controls for 17 risk-associated single nucleotide polymorphisms (SNPs) reported by the IMSGC. Of 16 SNPs that passed quality control filters, four, each corresponding to a different non-human leukocyte antigen (HLA) gene, were associated with disease susceptibility: KIAA0350 (rs6498169) P=0.001, IL2RA (rs2104286) P=0.033, RPL5 (rs6604026) P=0.041 and CD58 (rs12044852) P=0.042. There was no association (P=0.58) between rs6897932 in the IL7R gene and the risk of MS. No interactions were detected between the replicated IMSGC SNPs and HLA-DRB1*15, gender, disease course, disease progression or age-at-onset. We used a novel Bayesian approach to estimate the extent to which our data increased or decreased evidence for association with the six most-associated IMSGC loci. These analyses indicated that even modest P-values, such as those reported here, can contribute markedly to the posterior probability of 'true' association in replication studies. In conclusion, these data provide support for the involvement of four non-HLA genes in the pathogenesis of MS, and combined with previous data, increase to genome-wide significance (P=3 x 10(-8)) evidence of an association between KIAA0350 and risk of disease.

Reflections on treatment strategies for palliative chemotherapy of pancreatic cancer.

Following our concept of efficacy-orientated sequential polychemotherapy, we report on the results of palliative chemotherapy in 69 patients suffering from exocrine pancreatic cancer, admitted to our unit in 2004. Evaluation of tumor response was mainly based on the serum courses of the tumor markers CA 19-9 and CEA; in addition, the modern imaging methods CT or MRT, including MRCP and MR-angiography, were performed bi-monthly. The median survival of the 69 patients (65% metastasized stages) was 16 months. The median survival increased with the number of effective treatment sequences, for the whole group from 5 to 10 and 23 months in relation to 0, 1 and > 1 effective sequences respectively. The results support our concept of EOSPC in pancreatic cancer patients, compared to clinical studies following protocols with only 1 treatment sequence and median survival rates of no more than 6-9 months. Compared to the efficacy-orientated sequential polychemotherapy (EOSPC) concept, which does not exclude but also allows the inclusion of clinical trials for further evaluation of new drugs or drug combinations, the common practice looking for survival in studies following protocols with only 1 treatment sequence might represent a negative predictive factor with respect to overall survival, as can be demonstrated by a comparison of our data with relevant recent literature. Our results further indicate that the interest of the clinicians and companies should not be focused only on first-line therapies, but also on 2nd- and 3rd-line strategies, as in our patients a second- and third-line therapy could be started in 73% and 68% of the patients respectively.

Further evidence for prolongation of survival of pancreatic cancer patients by efficacy orientated sequential polychemotherapy (EOSPC) based on serial tumor marker determinations (CA 19-9/CEA).

The results of palliative chemotherapy in 55 patients suffering from exocrine pancreatic cancer are reported, following our concept of efficacy orientated sequential polychemotherapy (EOSPC). Tumor answer/regression was mainly analyzed on the basis of the serum courses of the tumor markers CA 19-9 and CEA. Up to four different treatment trials were tried in the individual patients. The results confirm previously published data: a prolongation of survival in relation to the number of effective treatments (CR/PR/MR/SD vs. PD). The median survival of the whole group of patients (n=55, including n=39 patients with distant metastasis) was 12 months. The results support our concept of EOSPC in pancreatic cancer patients in order to improve survival. Furthermore, the data should stimulate attention not only on new and potentially more effective 1st- line regimens, but also to effective 2nd- and/or 3rd-line treatments. Moreover, the results should encourage clinicians to rediscuss the actual concepts of prospective therapeutical trails mainly based on analyzing the effects of single agents or drug combinations on survival. Furthermore, a comparison of 1st-line treatments with gemcitabine as monotherapy, and in combination with mitomycin-C, confirms that the combination of gemcitabine + mitomycin-C seems to be more active than gemcitabine monotherapy and that this combination might also be of value as 2nd-line therapy after gemcitabine monotherapy.

Tumor marker determination after orthotopic heart transplantation.

BACKGROUND: Because the risk of developing malignant tumors after heart transplantation is approximately 100-fold higher, methods for rapid diagnosis must be developed to allow early and aggressive treatment in these patients. Although tumor markers have been used frequently for surveying already detected cancer, we studied their value in screening for tumors in heart transplant patients. METHODS: The levels of the tumor markers CEA, CA19-9, CA125, CA72-4, TPA, TPS, and CYFRA 21-1 were determined prospectively in 3-month intervals in 91 heart transplant patients between 1993 and 1998. RESULTS: In eight patients a definite diagnosis of cancer was made during the marker survey (mean observation time 2.85 +/- 1.3 years), including bronchogenic carcinoma in six, renal carcinoma in one, and colon cancer in one. All patients with bronchogenic carcinoma were smokers. The markers had a sensitivity below 60% to detect cancer. Given a 2-fold cutoff level (10 ng/mL), the CEA was the only marker with sufficient specificity (93.8%, only one false-positive result). Two patients were symptom-free even though they had elevated CEA levels. In one of those patients, disseminated intractable cancer was diagnosed at first evaluation, whereas no tumor was found in the other case at first evaluation. Subsequently, by means of fluorodeoxyglucose positron emission tomography, a hypermetabolic region was found in the right upper mediastinum. Control computed tomographic scan 4 weeks after the first investigation showed disseminated intractable disease also in this patient. Another heart transplant patient with colon cancer showed a normalization of the CEA after hemicolectomy and an increase in the CEA when liver dissemination developed. There was a relationship between cardiac death and CA125 and TPS in some heart transplant patients. CONCLUSIONS: We conclude that the CEA is the only tumor marker with adequate sensitivity and specificity to detect subclinical malignancies in the follow-up of heart transplant patients. However, because of several limitations (limited diagnostic and therapeutic possibilities and enormous costs), we cannot recommend screening by tumor markers on a regular basis. Because of the elevated risk of cancer in patients who had organ transplantation, further prophylactic measures, especially smoking cessation programs, must be developed. Once a malignancy is diagnosed, tumor markers can help target clinical decisions. Additionally, nonspecific increases in CA125 and TPS levels might be related to nonmalignant circulatory disturbances and cardiac death.

Atypical courses of serum tumor markers--4 case reports.

We report on 4 cancer patients with transient unspecific elevations of the serum tumor markers CA 19-9, CEA, CA 125 and CA 72-4, respectively. In one patient cholangitis due to biliary obstruction induced a significant transient increase of CA 19-9, in another patient HUS, probably as a severe complication after Mitomycin-C + Gemcitabine therapy resulted in a significant increase of serum CA 125. One patient demonstrated an extensively elevated and inexplicable serum CA 19-9 concentration (9450 u/ml) during a period of abdominal pain with continuous decrease and finally normalization within the following 5 years. Also inexplicable is an unexpected remittent increase of serum CA 72-4 in the course of chemotherapy after gastrectomy for gastric carcinoma. The presented data underline the necessity of interpreting serum courses of tumor markers only in the light of all available clinical data, imaging data and other laboratory tests in order to avoid misinterpretations.

CEA, TPS, CA 19-9 and CA 72-4 and the fecal occult blood test in the preoperative diagnosis and follow-up after resective surgery of colorectal cancer.

In a prospective clinical study we examined the diagnostic procedures used in the preoperative diagnosis of colorectal cancer patients (n = 176) and the value of supplementation of standard diagnostic methods (clinical investigation, colonoscopy, barium enema, ultrasound, computer tomography) with a test for occult fecal blood (FOBT) and an expanded tumor marker panel (CA 19-9, TPS and CA 72-4 in addition to CEA) in the postoperative follow-up (n = 116, mean follow-up 21 months). Preoperative diagnosis based on colonoscopy/barium enema, followed by histology and the imaging methods, in most cases US and/or CT. Patients with postoperative stage Dukes D and after palliative surgery were excluded from the follow-up study (n = 43). The patients were seen every three months (clinical investigation, US, CT, tumor markers, FOBT) within the first two postoperative years and every half a year thereafter. 83 of the 116 patients (16%) developed a recurrent disease and 5 of them could be reoperated with curative intention. In addition to the 19 patients 14 simultaneously admitted patients with recurrence of colorectal cancer (total n = 33) were studied. The results of our study analyzing the sensitivity and specificity of colonoscopy, tumor, markers and the FOBT in the preoperative and postoperative phases as well as in the diagnosis of recurrent disease of colorectal cancer confirms the view that FOBT and tumor markers cannot replace endoscopic and imaging methods. However they support the concept, that diagnosis and follow-up of colorectal cancer should be based on a combination of clinical investigation and imaging methods (US, CT etc. and endoscopic and/or x-ray examination) with supplementation by FOBT and determination of tumor markers, mainly CEA. In the case a patient is asking for prognostic and recurrence information as early and as valid as possible we currently recommend the following procedure for the first two years after surgery: every three months the determination of tumor markers, FOBT as well as ultrasound of the upper abdomen and CT of the lower abdomen and every half year a total colonoscopy. The question of whether this program will also have a therapeutical relevance depends on several factors like the personal experience and concepts of the consulting surgeons and oncologists and also on the tasks and duties which are considered worthy by the patient for his further life if confronted with the diagnosis of recurrent colorectal cancer.

Fluctuations of tumor markers in heart failure patients pre and post heart transplantation.

BACKGROUND: Elevated plasma levels of tumor markers may be caused by diseases other than malignancy, i.e. kidney, liver or circulatory disturbances. These conditions are not well defined, especially since there are only sparse reports on fluctuations of tumor markers related to cardiac function. PATIENTS AND METHODS: During our routine pre- and postoperative follow-up tumor marker determinations in heart failure patients were made in order to screen for possible occult neoplasm's which may either be a contraindication or a sequela of heart transplantation. The markers CA 12-5, CEA, CA 19-9, CA 72-4, TPA, TPS and CYFRA 21-1 were determined at three month intervals, besides clinical examination and hemodynamic measurements in a total of n = 118 patients pre- and n = 74 patients post heart transplantation. RESULTS: The results were grouped according the clinical status (NYHA-stage 1-4): CA12-5 (29.4 +/- 40.63 omega 151, 174 +/- 345 and 491 +/- 633 U/ml, p < 0.001 between all groups) and TPS (64 +/- 32, 118 +/- 153, 163 +/- 311 and 181 +/- 232 U/ml, p = 0.06 between all groups) were increasingly elevated in NYHA stages 1, 2, 3 or 4 respectively. A direct correlation to right atrial pressure (r = 0.41, p < 0.0001) and pulmonary capillary wedge pressure (r = 0.27, p < 0.001) was only found for CA 12-5. After heart transplantation a normalization of elevated pre-OP levels could be found. Comparable to heart failure patients poor graft function was also associated with elevated levels of CA 12-5 (113 +/- 99 vs 21.6 +/- 31 U/ml, p < 0.0001), CA 72-4 (8.4 +/- 3 vs 3.6 +/- 4, U/ml p = 0.03) and TPS (154 +/- 133 vs 66 +/- 28 U/ml, p < 0.001). The individual time course of the markers, especially of CA 12-5, correlated nicely to clinical events and hemodynamic measurements in some patients. Another finding was that CYFRA 21-1 levels were correlated to renal function. CEA, CA 19-9 and CYFRA 21-1 serum levels were not influenced by circulatory disturbances. CONCLUSION: We concluded that the tumor markers CA 12-5 and TPS (but not CEA, CA 19-9 and CYFRA 21-1) are associated with congestion and the clinical course of heart failure and HTx patients. These "nonspecific" changes have to be considered when tumor markers are determined in cancer patients with heart failure. Whether CA 12-5 blood levels may yield additional prognostic information in the management of cardiovascular patients has to be determined in further studies.

Improvement of survival by efficacy orientated sequential polychemotherapy of exocrine pancreatic cancer.

Results of palliative chemotherapy in 104 patients suffering from exocrine pancreatic carcinomas are presented. First-line therapy included intraarterial approaches with gemcitabine + mitomycin-C and intravenous systemic treatments with gemcitabine, gemcitabine + mitomycin-C and oxaliplatin, respectively. In addition, it was the aim to improve survival by adding second- and third-line chemotherapies, mainly including high dose 5-FU/FA and irinotecan resp. alone or in combinations. Follow-up included clinical investigations, imaging methods and determination of tumor markers. Evaluation of efficacy followed the WHO guidelines. The results indicated the intraarterial locoregional treatment of exocrine pancreatic cancer with a combination of mitomycin-C + gemcitabine as a highly effective treatment modality with PR + CR of 40% measured by imaging methods and 81% analysed by tumor marker determinations. The survival analyses suggested relevant prolongation of survival in relation to the number of effective second- and/or third-line therapies (0/1/> 1) with median survival--based on the imaging data--of 7, 11 and 20 months for Mo tumors and 3, 8 and 14 months for tumor diseases with liver metastases at time of admission, respectively. Relevant preconditions for second- and/or third-line therapies of pancreatic carcinomas are given by more or less effective first-line treatment modalities of this cancer disease on the one hand and by the actual diagnostic aids allowing the beginning of first-line therapy as well as the detection of recurrence early enough to try a second- or third-line therapy before clinical/ethical aspects prevent further antitumoral treatment trials in the individual patient.

P53 auto-antibodies in the sera of patients with oral squamous cell carcinoma.

AIM: To investigate the sera of patients with oral squamous cell carcinoma (OSCC) for the existence of p53 auto-antibodies. MATERIAL AND METHODS: The sera of thirty-nine OSCC-patients were investigated. All samples were from untreated patients with no history of another neoplastic disease. The sera of nine healthy subjects served as controls. RESULTS: P53 auto-antibodies were not detected both in all healthy subjects and in 20.6% OSCC-patients with their disease at an advanced stage. We prove that the extinction rates for p53 auto-antibodies in OSCC are very weak in the majority of investigated sera (50%) and are not related to tumour stage. CONCLUSION: It is unlikely that p53 auto-antibodies can serve as a prognostic marker of OSCC.

TNM staging, histopathological grading, and tumor-associated antigens in patients with a history of mucoepidermoid carcinoma of the salivary glands.

BACKGROUND: The aim of this study was to evaluate the TNM categories and histopathological grading as prognostic factors in mucoepidermoid carcinoma (MEC). In addition, the study was designed to provide baseline data on levels of tumor-associated antigens (TAA) in sera of MEC patients. MATERIALS AND METHODS: Fifty-nine patients with MEC of the salivary glands were evaluated. RESULTS: Reclassified TNM stage, at the time of initial diagnosis, varied considerably. In disease-free patients, none of the tested sera were TAA elevated above the cut-off levels. Our patients who died of tumor metastasis had all been classified as stage III or IV at the time of initial diagnosis. Distant metastases are rarely found even decades after surgical therapy. CONCLUSIONS: Long-term follow-up is recommended for patients with MEC of the salivary glands. TAA are not elevated in disease-free patients. The value of TAA in the monitoring of MEC patients remains to be evaluated in further studies.

Sequential polychemotherapy in exocrine pancreatic cancer.

The results of palliative chemotherapy in 162 patients suffering from exocrine pancreatic cancer are presented. They are mainly discussed with respect to the possibility of improving survival of exocrine pancreatic cancer patients by an efficacy-orientated sequential polychemotherapy (EOSP). In about 40% of the patients treated between 1998 and 2001, sequential chemotherapy induced more than one effective treatment in the case that SD after a progressive prephase as well as MR, PR and CR are considered as antitumoral efficacy. Sequential polychemotherapy seems to be able to prolong the survival of these patients. The whole group of patients showed a 1-year survival of 56% and a 2-year survival of 16%. Especially in the case of metastasized tumor disease (M1), sequential polychemotherapy seems to be able to prolong survival: 45% of the metastasized tumor patients survived more than 1 year, 12% more than 2 years. The median survival for the whole group of locally advanced tumors was 15 months and the median survival for the whole group of metastasized tumors was 8 months. The results should stimulate clinicians to try palliative chemotherapy for pancreatic cancer more actively than before and to rediscuss the actual concepts of prospective therapeutical trials mainly based on analysing the effects of single agents or drug combinations on survival.

Radioimmunotherapy of xenografts of human pancreatic carcinomas--intravenous and intratumoral application of 131I-labelled monoclonal antibodies.

The effects of radioimmunotherapy were tested in xenografts of 2 different human pancreatic carcinomas comparing the intravenous and intratumoral application. On principle, intravenous injections of high doses of 131I-anti-CA 19-9 or -BW 494/32 may inhibit tumor growth. In view of the low direct radiation dose (360-2100 rad), however, other factors than direct toxic effects have to be discussed, e.g. systemic effects due to the high whole-body irradiation. Intratumoral application, however, may induce tumor regression or growth inhibition due to the high local irradiation dose. Consequently, this treatment modality might be of clinical value at least in some patients.

Immunoscintigraphy with combinations of various monoclonal antibodies--studies on xenografts of human gastrointestinal carcinomas.

In order to investigate whether combinations of monoclonal antibodies (MAbs) allow a more sensitive and valid localisation of tumors by immunoscintigraphy compared to the application of single MAbs we injected 3.7 MBq/animal of various 131I-labelled MAbs (anti-CA 19-9, -CA 125, -CEA, BW 494/32, 431/31) or equivalent combinations thereof into NuNu-Balb-C mice bearing xenografts of human gastrointestinal tumors. In addition, "dose response curves" were calculated in order to evaluate the results for different total doses. As parameters we mainly used quality of the scans, fractional uptake of injected dose and tumor/blood or tumor/organ ratios. The results do not support the concept that "cocktails" of MAbs improve the results of immunoscintigraphy. In contrast, a single MAb should be used for clinical immunoscintigraphy, preferably the most appropriate one according to the results of serum determinations of the corresponding tumor-associated antigens or of immunohistochemistry. Cocktails or consecutive applications of different MAbs for immunoscintigraphy should be restricted to cases without dominant tumor-associated antigen and corresponding MAb, respectively, and to patients in whom a first trial with a first single MAb failed.

The current state of multiple sclerosis genetic research.

INTRODUCTION: Multiple sclerosis (MS) is the most common genetic disease of the nervous system with onset usually in young adulthood. Four genome-wide searches in different Caucasian populations for MS susceptibility loci have been performed, but none reported any linkage at a level that would be regarded as significant according to current criteria. Significant linkage of MS to allelic variants of the major histocompatibility (MHC) locus on chromosome 6p21 has been established although its overall contribution to MS susceptibility has proven difficult to quantify. The objective of this review is not only to provide the reader with an update of MS genetics research, but also to provide a basic knowledge of the techniques being employed to map MS susceptibility genes. The different methodologies are discussed, and specific studies are reviewed in context. METHODS: This review is based on findings from original articles, however, the results of recent candidate gene studies are intended to update previous review articles. RESULTS: There remains no concrete non-MHC locus for MS, although there are enough findings of sufficient interest to warrant further investigation and optimism. Stratification of genome scan data based on MHC class II suggests that it interacts differentially with non-MHC loci and that it contributes moderately to disease susceptibility. Candidate gene studies have continued to return negative and ambiguous results, and follow-up fine mapping of suggestive linkages from the UK genome scan has proven unsuccessful in identifying significant linkages. Genetic analysis of crosses between mouse strains that are differentially susceptible to experimental allergic encephalomyelitis (EAE) has yielded linkages corresponding to putative MS susceptibility loci. However, recent successes in transgenic mice may provide an alternative to EAE, regarded by some as a poor model of MS. CONCLUSION: The first whole genome search for a common human disease was performed over five years ago, and it is now clear, from the lack success in this field, that the genetic complexity of these traits has been underestimated. The genome-wide searches for MS susceptibility genes have suffered from insufficient statistical power, which has probably been compounded by disease and genetic heterogeneity. Studies in isolated populations and better laboratory and clinical definitions of disease are both steps in the right direction to solving these problems. Not withstanding the negative effects of genetic heterogeneity, pooling of resources for meta-analyses may provide the increase in statistical power required for detection of loci that exert a moderate or small effect on disease predisposition.