We report on a mother and son with Cowden syndrome and a PTEN mutation. The boy also exhibits autistic behavior and mental retardation, while his mother has a normal intelligence and social interaction pattern. We review the scanty literature data on the association of Cowden syndrome and autism and emphasize that the association of progressive macrocephaly and pervasive developmental disorder seems to be an indication for screening for PTEN mutations.

smMIP-based genetic testing enables automated and reliable analysis of the coding sequences of BRCA1 and BRCA2. The use of single-molecule tags, double-tiled targeted enrichment, and capturing and sequencing in duplo, in combination with automated library preparation and data analysis, results in a robust process and reduces routine turnaround times. Furthermore, smMIP-based copy number variation analysis could make independent copy number variation tools like multiplex ligation-dependent probes amplification dispensable.

Breast cancer is the most common malignancy in women. A family history of breast cancer has long been recognized as one of the strongest risk factors for the disease and it is estimated that 5-10% of all breast cancer cases can be attributed to inherited autosomal dominant susceptibility genes. Two genes involved in hereditary breast and/or ovarian cancer syndromes, BRCA1 and BRCA2, were cloned (Miki et al, 1994;Wooster et al, 1995;Tavtigian et al, 1996). Initially, reports on extended high-risk families suggested that germline mutations in BRCA1 would account for about 45% of the hereditary site-specific breast cancer families, and for more than 80% of the hereditary breast and ovarian cancer families (Easton et al, 1993). Similar studies predicted the involvement of BRCA2 in the majority of non-BRCA1-linked breast cancer families (Wooster et al, 1994). Recent studies, however, show that germline mutations in BRCA1 and BRCA2 are only associated with approximately half of all hereditary breast and/or ovarian cancer, and that this proportion varies widely among populations (for review see Szabo and King, 1997).Most of our current knowledge on genetic predisposition by BRCA1 or BRCA2 is based on families with multiple cases of breast and/or ovarian cancer. Few data are available on less extended families, i.e. with only three to five individuals with breast and/or ovarian cancer, although they form the majority of families seeking genetic advice in the family cancer clinics.In this study we determined the frequency of both BRCA1 and BRCA2 germline mutations in relatively small families whose cancer risk was evaluated at our family cancer clinics. Striking differences in the prevalence of BRCA1 or BRCA2 mutations were found in families with only breast cancer when families were classified according to the presence or absence of bilateral breast cancer and the age of diagnosis of the youngest patient. MATERIALS AND METHODS Study populationSelf-referred or physician-referred breast and/or ovarian cancerprone families visiting the family cancer clinics at The University Hospital Nijmegen and The Netherlands Cancer Institute were the subjects of this study. For the categorization of the families, first-, second-and third-degree relatives of the person tested were taken into consideration. The number of affected individuals varied between three and nine (mean 4.3; median 4) in families with at least one case of ovarian cancer and between three and five (mean of 3.6; median 3) in families without ovarian cancer. If possible, the patients with the highest prior probability of carrying a mutation in one of the susceptibility genes were examined. In 93 families one or more patients with a history of breast and/or ovarian cancer were investigated. In 11 families only unaffected firstdegree relatives could be sampled for various reasons. On average, 1.4 individuals were tested in each family. For most patients clinical archives and pathological records were retrieved and Summary For families with a small number of cases of br...

BACKGROUND: Dideoxy-based chain termination sequencing developed by Sanger is the gold standard sequencing approach and allows clinical diagnostics of disorders with relatively low genetic heterogeneity. Recently, new next generation sequencing (NGS) technologies have found their way into diagnostic laboratories, enabling the sequencing of large targeted gene panels or exomes. The development of benchtop NGS instruments now allows the analysis of single genes or small gene panels, making these platforms increasingly competitive with Sanger sequencing.

Background: Indirect alternatives to sequencing as a method for mutation scanning are of interest to diagnostic laboratories because they have the potential for considerable savings in both time and costs. Ideally, such methods should be simple, rapid, and highly sensitive, and they should be validated formally to a very high standard. Currently, most reported methods lack one or more of these characteristics. We describe the optimization and validation of conformation-sensitive capillary electrophoresis (CSCE) for diagnostic mutation scanning. Methods: We initially optimized the performance of CSCE with a systematic panel of plasmid-based controls. We then compared manual analysis by visual inspection with automated analysis by BioNumerics software (Applied Maths) in a blinded interlaboratory validation with 402 BRCA1 (breast cancer 1, early onset) and BRCA2 (breast cancer 1, early onset) variants previously characterized by Sanger sequencing. Results: With automated analysis, we demonstrated a sensitivity of >99% (95% CI), which is indistinguishable from the sensitivity for conventional sequencing by capillary electrophoresis. The 95% CI for specificity was 90%–93%; thus, CSCE greatly reduces the number of fragments that need to be sequenced to fully characterize variants. By manual analysis, the 95% CIs for sensitivity and specificity were 98.3%–99.4% and 93.1%–95.5%, respectively. Conclusions: CSCE is amenable to a high degree of automation, and analyses can be multiplexed to increase both capacity and throughput. We conclude that once it is optimized, CSCE combined with analysis with BioNumerics software is a highly sensitive and cost-effective mutation-scanning technique suitable for routine genetic diagnostic analysis of heterozygous nucleotide substitutions, small insertions, and deletions.