Dorthe Gylling Crüger

Fertility and pregnancy outcome in Danish women with Turner syndrome

The aim of the investigation was to study fertility in Danish women diagnosed with Turner syndrome (TS), and to describe their offspring. In total, 410 women in the fertile age were registered in the Danish Cytogenetic Central Register with TS between January 1973 and December 1993. Their karyotype were as follows: 49% with 45,X, 23% with mosaicism and a structural abnormality of the second X, 19% with 45,X/46,XX mosaicism, and 9% with 46,XX and a structural abnormality of the second X. Thirty‐three women, one with 45,X, 27 with mosaicism and 5 with 46,XX and a structural abnormality of the second X, gave birth to 64 children. Two women had become pregnant after in vitro fertilization, including a woman with 45,X after an egg donation. Thus, 31 women(7.6%) had achieved at least one spontaneous pregnancy, but 48% of the fertile women registered with 45,X/46,XX had 45,X in less than 10% of the analysed cells. Twenty‐five of the 64 children had a chromosome analyzed. Six of the 25 examined children, including three siblings, had chromosomal aberrations. No case of Downs syndrome was present, and only two children had malformations. Fertility in women registered with TS is higher than earlier reported. However, only women with 45,X/46,XX mosaicism or 46,XX and structural abnormality of the second X, gave birth to live children after spontaneous pregnancies.

Risk-reducing mastectomy and salpingo-oophorectomy in unaffected BRCA mutation carriers: uptake and timing.

Skytte A‐B, Gerdes A‐M, Andersen MK, Sunde L, Brøndum‐Nielsen K, Waldstrøm M, Kølvraa S, Crüger D. Risk‐reducing mastectomy and salpingo‐oophorectomy in unaffected BRCA mutation carriers: uptake and timing.

Genetic analysis of males from intracytoplasmic sperm injection couples

A total of 392 men referred for intracytoplasmic sperm injection (ICSI) participated in genetic analysis. The control group consisted of 100 normal fertile males. Chromosome and DNA analyses were performed to investigate the frequency of Y‐chromosome microdeletions and CFTR mutations (the controls underwent DNA analysis only). An abnormal karyotype was found in 4.6% of all males, but the frequency among men with azoospermia was higher, at 11.7%. Y‐chromosome microdeletions were found only among men with azoospermia (6.5%) and men with extreme oligospermia (2%). Compound heterozygosity for CFTR mutations was found in men with azoospermia (3.9%) and congenital bilateral absence of vas deferens (CBAVD) only. We conclude that all couples referred for ICSI should be offered chromosome analysis. DNA analysis for Y‐chromosome microdeletions should be reserved for men with azoospermia or extreme oligospermia (<1 × 106 spermatozoa). Analysis for CFTR mutations should be limited to those with obstructive azoospermia or those with a family history of cystic fibrosis.

A BAP1 Mutation in a Danish Family Predisposes to Uveal Melanoma and Other Cancers

Truncating germline mutations in the tumor suppressor gene BRCA-1 associated protein-1 (BAP1) have been reported in families predisposed to developing a wide range of different cancer types including uveal melanoma and cutaneous melanoma. There has also been an association between amelanotic tumor development and germline BAP1 mutation suggesting a possible phenotypic characteristic of BAP1 mutation carriers. Though there have been many types of cancer associated with germline BAP1 mutation, the full spectrum of disease association is yet to be ascertained. Here we describe a Danish family with predominantly uveal melanoma but also a range of other tumor types including lung, neuroendocrine, stomach, and breast cancer; as well as pigmented skin lesions. Whole-exome sequencing identified a BAP1 splice mutation located at c.581-2A>G, which leads to a premature truncation of BAP1 in an individual with uveal melanoma. This mutation was carried by several other family members with melanoma or various cancers. The finding expands on the growing profile of BAP1 as an important uveal and cutaneous melanoma tumor suppressor gene and implicates its involvement in the development of lung, and stomach cancer.

Strategy in clinical practice for classification of unselected colorectal tumours based on mismatch repair deficiency.

Objective  Deficiency of DNA mismatch repair (MMR) causes microsatellite instability (MSI) in a subset of colorectal cancers. Patients with these tumours have a better prognosis and may have an altered response to chemotherapy. Some of the tumours are caused by hereditary mutations (hereditary nonpolyposis colon cancer or Lynch syndrome), but most are epigenetic changes of sporadic origin. The aim of this study was to define a robust and inexpensive strategy for such classification in clinical practice.

Breast cancer after bilateral risk-reducing mastectomy

Skytte A‐B, Crüger D, Gerster M, Lænkholm A‐V, Lang C, Brøndum‐Nielsen K, Andersen MK, Sunde L, Kølvraa S, Gerdes A‐M. Breast cancer after bilateral risk‐reducing mastectomy.

Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population

An increasing number of mismatch-repair (MMR) gene mutations have been identified in hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome. This study presents the population-based Danish MMR gene mutation profile, which contains 138 different MMR gene alterations. Among these, 88 mutations in 164 families are considered pathogenic and an additional 50 variants from 76 families are considered to represent variants of unknown pathogenicity. The different MMR genes contribute to 40% (MSH2), 29% (MLH1), and 22% (MSH6) of the mutations and the Danish population thus shows a considerably higher frequency of MSH6 mutations than previously described. Although 69/88 (78%) pathogenic mutations were present in a single family, previously recognized recurrent/founder mutations were causative in 75/137 (55%) MLH1/MSH2 mutant families. In addition, the Danish MLH1 founder mutation c.1667+2_1667_+8TAAATCAdelinsATTT was identified in 14/58 (24%) MLH1 mutant families. The Danish Lynch syndrome population thus demonstrates that MSH6 mutations and recurrent/founder mutations have a larger contribution than previously recognized, which implies that the MSH6 gene should be included in routine diagnostics and suggests that directed analysis of recurrent/founder mutations may be feasible e.g. in families were diagnostic material is restricted to archival tissue.

Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a population-based cohort study in Denmark.

OBJECTIVES:In a population-based, well-defined group of patients first regarded as having pancreatitis of unknown origin (PUO), we identified, described, and compared the clinical and genetic aspects of patients with hereditary pancreatitis (HP) and with cystic fibrosis transmembrane conductance regulator gene (CFTR) and serine protease inhibitor Kazal type 1 gene (SPINK1) mutations with patients who retained the diagnosis of true idiopathic pancreatitis (tIP) after genetic testing for HP, SPINK1, and CFTR mutations.METHODS:Patients with PUO were identified in the Danish National Registry of Patients or were referred by clinicians. DNA from blood was analyzed for cationic trypsinogen (PRSS1), SPINK1, and CFTR mutations. Considering the diagnosis of HP, a pedigree was drawn for each patient.RESULTS:A genetic mutation was found in 40% of 122 patients with PUO. After testing first-degree relatives of the 18 initially identified HP patients, 38 HP patients in total were identified, and 28 patients had SPINK1–CFTR mutations. Among HP patients, no p.N29I mutations were found and the p.A16V mutation was more frequent than previously reported, 45 and 32% had exocrine and endocrine insufficiency, respectively, and among tIP patients 9 and 12%, respectively. Pancreatic cancer was diagnosed in 5% of the HP families.CONCLUSIONS:The genotype of the Danish population with HP differs from that of previously described cohorts. The occurrence of exocrine and endocrine insufficiency is higher among patients with HP than in patients with SPINK1–CFTR mutations and tIP, and more HP families develop pancreatic cancer. Genetic testing thus helps to predict the prognosis of the pancreatitis.

Evaluation of two different models to predict BRCA1 and BRCA2 mutations in a cohort of Danish hereditary breast and/or ovarian cancer families

To meet the increasing demand for BRCA1 and BRCA2 mutation analysis, a robust system for selecting families who have a higher chance of a mutation has become important. Several models have been developed to help predict which samples are more likely to be mutation positive than others. We have undertaken a complete BRCA1 and BRCA2 mutation analysis in 267 Danish families with high‐risk family history. We found deleterious mutations in 28% (76) of the families, 68% (52) of those in BRCA1 and 32% (24) in BRCA2. We compared our results with two popular manual models developed to estimate the chance of a positive result. One is the recently published Manchester model and the other is the Frank 2 model updated by Myriad Genetic Laboratories, Inc. Neither of the models would have suggested screening all mutation‐positive samples. The Manchester model would have suggested screening 124 of the families in the cohort, thereby detecting 54 of 76 mutations (sensitivity 71%; specificity 63%), whereas the Frank 2/Myriad model would have found 60 of 76 mutations by screening 169 samples if a 10% likelihood was adapted (sensitivity 79%; specificity 43%). The updated Manchester model suggested screening 172 families whereby 64 mutations would have been detected (sensitivity 84%; specificity 44%). We conclude that although both models would have reduced the number of samples screened significantly, up to 28% of the mutations would not have been found by applying these models to this Danish cohort of families. This raises the question whether models designed for specific populations can be used in a wider setting.

Population-based survey of cancer risks in chromosome 3 translocation carriers

Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be associated with germline mutations in a number of genes. Twelve different constitutional translocations involving chromosome 3 have also been described in association with inherited RCC. In some families the lifetime risk of RCC in chromosome 3 translocation carriers has been estimated to be more than 80%; however the cancer risks in patients with chromosome 3 translocations not ascertained because of a family history of RCC are not well defined. We report a retrospective population‐based study using Danish national cytogenetic and cancer registries to clarify tumor risks associated with constitutional translocations involving chromosome 3. We identified 222 (105 females, 117 males) individuals with a constitutional chromosome 3 translocation and compared their cancer risks to those of the Danish population. None of the chromosome 3 translocation carriers had developed RCC at the time of study (female 95% CIs 0.000–0.042, male 95% CIs 0.000–0.038) (P = 1.0 and P = 0.498 for females and males compared to Danish population). Fourteen translocation carriers had developed cancer but there was no evidence of an excess of early onset disease and lifetime cancer risks in chromosome 3 translocation carriers were similar that in the Danish population. There was no association between cancer risk and location of the chromosome 3 breakpoint (HR = 1.322, P = 0.673). These findings suggest that, in the absence of a family history of RCC or evidence of disruption of a specific tumor suppressor gene, chromosome 3 translocations carriers are not at high risk of developing RCC.