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Insights from psychiatric genetics research and large international psychiatric genetics consortia are promising but still remain outside the realm of clinical practice.brAIM: To provide an overview of developments in the field of psychiatric genetics; and to offer guidance for health professionals how to assess and manage clinical implications of these developments.brMETHOD: In this review, we address: recent developments in psychiatric genetics, with a focus on polygenic risk scores (PRS); ethical dilemmas associated with clinical application of PRS; and basic principles of genetic counseling for psychiatric disorders.brRESULTS: PRS are not yet ready for implementation in clinical practice because of limited predictive value and poor generalizability. In addition, it is still unclear how genetic risk and PRS can be communicated clearly to patients and families.brCONCLUSION: Advances in psychiatric genetics and increased availability of genetic risk scores may lead to questions from patients and families coping with psychiatric illness. These questions may be best addressed using psychiatric genetic counseling techniques. We recommend that psychiatrists have some basic knowledge of psychiatric genetics and know how to refer their patients to a clinical geneticist. Implementing a psychiatric genetics theme in training and education may be helpful.br.

Background Pre-test genetic counseling for patients with breast cancer is increasingly being provided by nongenetic healthcare professionals. We evaluated the attitudes, knowledge, and self-efficacy of surgeons, oncologists, and nurses regarding mainstream genetic testing and the feasibility to incorporate pre-test genetic counseling into routine care. Methods We offered an online training to healthcare professionals from 13 hospitals and implemented a mainstream genetic testing pathway in 11/13 (85%) hospitals. Questionnaires were sent before (T0) and 6 months after (T1) completing the training. Those who did not complete the training received a questionnaire to assess their motivations. Results In 11 hospitals, 80 (65%) healthcare professionals completed the training, of whom 70 (88%) completed both questionnaires. The attitudes, (perceived) knowledge and self-efficacy of healthcare professionals were high both at baseline and 6 months after completing the training. After 6 months, their perceived knowledge about the advantages and disadvantages of a genetic test and implications for family members had significantly improved (p = 0.012 and p = 0.021, respectively). For the majority (89%), the time investment for pre-test genetic counseling was less than 15 min per patient and as expected or better. Healthcare professionals considered the total time investment feasible to incorporate mainstream genetic testing into their daily practice. The main barrier to complete the training was lack of time. The online training was considered useful, with a rating of 8/10. Conclusion Surgical oncologists and nurses in breast cancer care feel well-equipped and motivated to provide pre-test genetic counseling after completion of an online training module.

Identifying a hereditary colorectal cancer (CRC) syndrome or familial CRC (FCC) in a CRC patient may enable the patient and relatives to enroll in surveillance protocols. As these individuals are insufficiently recognized, we evaluated an online family history tool, consisting of a patient-administered family history questionnaire and an automated genetic referral recommendation, to facilitate the identification of patients with hereditary CRC or FCC. Between 2015 and 2016, all newly diagnosed CRC patients in five Dutch outpatient clinics, were included in a trial with a stepped-wedge design, when first visiting the clinic. Each hospital continued standard procedures for identifying patients at risk (control strategy) and then, after a predetermined period, switched to offering the family history tool to included patients (intervention strategy). After considering the tool-based recommendation, the health care provider could decide on and arrange the referral. Primary outcome was the relative number of CRC patients who received screening or surveillance recommendations for themselves or relatives because of hereditary CRC or FCC, provided by genetic counseling. The intervention effect was evaluated using a logit-linear model. With the tool, 46/489 (9.4%) patients received a screening or surveillance recommendation, compared to 35/292 (12.0%) in the control group. In the intention-to-treat-analysis, accounting for time trends and hospital effects, this difference was not statistically significant (p = 0.58). A family history tool does not necessarily assist in increasing the number of CRC patients and relatives enrolled in screening or surveillance recommendations for hereditary CRC or FCC. Other interventions should be considered. Electronic supplementary material The online version of this article (doi:10.1007/s10689-017-0041-7) contains supplementary material, which is available to authorized users.

Thanks to next-generation sequencing several genes can be examined in one go. Since this method has been introduced, the possibilities for DNA diagnostics in patients with dementia have increased tremendously in recent years.- DNA diagnostics is indicated for patients with an Alzheimer's disease diagnosis before they are 60 years old, for all patients with frontotemporal dementia and for patients with a positive family history.- For 15% of the patients who visited the Alzheimer centre of the VUmc, in Amsterdam, the Netherlands DNA diagnostics indicated a clear monogenic cause.- Although a hereditary cause of dementia is often a hard message for patients and their families, this knowledge often provides them with more clarity with respect to the diagnosis and the course of the disease. In addition, family members may choose to carry out presymptomatic DNA testing.- The therapeutical consequences of DNA diagnostics are currently minimal; several studies are being carried out internationally in this area.

Eight university medical centres in the Netherlands have established clinical genetic services. Patients receive intensive, and therefore costly, genetic counselling before genetic testing takes place. In recent years the number of patients referred to clinical genetic services has risen dramatically, creating waiting-list backlogs. Knowing your carrier status in hereditary cancers, for instance for a BRCA1/2 mutation, can have consequences for surveillance, treatment, and prevention; however, 90% of patients with breast cancer do not have a mutation. We, therefore, argue that the pathway to genetic testing should be reconstructed in order to safeguard timely and adequate genetic testing for an increasing number of patients. The treating physician should be able to request a DNA test in carefully-selected patient-populations, and only refer patients for genetic counselling after a positive finding. Prerequisites for this 'mainstream pathway' are adequate training for medical specialists, good communication with genetics' departments, and guaranteed referral in uncertain or complex cases.

Hoyeraal-Hreidarsson (HH) syndrome is a multisystem disorder affecting boys characterized by aplastic anaemia (AA), immunodeficiency, microcephaly, cerebellar-hypoplasia and growth retardation. Its pathogenesis is unknown. X-linked dyskeratosis congenita (DC) is an inherited bone-marrow-failure syndrome characterized by skin pigmentation, nail dystrophy and leucoplakia which usually develop towards the end of the first decade of life. AA occurs in >90% of cases of DC. We speculated that mutations in the gene responsible for X-linked DC (DKC1) may account for the HH syndrome, due to the phenotypic similarities between the disease in respect of AA and gender bias. We therefore analysed the DKC1 gene in two HH families. In one family a nucleotide change at position 361(A --> G) in exon 5 was found in both affected brothers; in the other family a nucleotide change at position 146(C --> T) in exon 3 was found in the affected boys. The finding of these two novel missense DKC1 mutations demonstrates that HH is a severe variant of DC. They also show that mutations in DKC1 can give rise to a very wide clinical spectrum of manifestations. Boys with unexplained AA or immunodeficiency should be tested for mutations in DKC1 even though they may lack diagnostic features of DC.

This study aims to give an overview of the number of prenatal tests for Huntington's disease (HD), test results, and pregnancy outcomes in the Netherlands between 1998 and 2008 and to compare them with available data from the period 1987 to 1997. A total of 126 couples underwent prenatal diagnosis (PND) on 216 foetuses: 185 (86%) direct tests and 31 (14%) exclusion tests. In 9% of direct tests the risk for the foetus was 25%. Four at-risk parents (4%) carried intermediate alleles. Ninety-one foetuses had CAG expansions ≥36% or 50% risk haplotypes: 75 (82%) were terminated for HD, 12 (13%) were carried to term; four pregnancies were miscarried, terminated for other reasons or lost to follow-up. Unaffected pregnancies (122 foetuses) resulted in the birth of 112 children. The estimated uptake of PND was 22% of CAG expansion carriers (≥36 repeats) at reproductive age. PND was used by two new subgroups: carriers of intermediate alleles and 50% at-risk persons opting for a direct prenatal test of the foetus. A significant number of HD expansion or 50% risk pregnancies were continued. Speculations were made on causative factors contributing to these continuations. Further research on these couples' motives is needed.

Three patients, a 45-year-old man, a 51-year-old woman and a 43-year-old woman, wanted to know whether they had a hereditary predisposition for cancer. The family of patient A fulfilled the clinical diagnostic criteria for hereditary non-polyposis colorectal carcinoma (HNPCC). The family of patient B fulfilled the clinical diagnostic criteria for hereditary breast/ovarian cancer (HBOC). The family of patient C did not completely fulfil the criteria for HBOC since only two family members had a confirmed diagnosis of breast cancer. In all three families, DNA-mutation analysis was performed. In families A and B no mutation was found. However, based on the family history, the diagnosis of hereditary cancer was made and recommendations for surveillance were given. After extensive counselling, one member of family B eventually decided to have prophylactic surgery performed. A few years later, a pathogenic mutation in BRCA2 was found in family B. In family C, an unclassified variant was found in BRCA1. Further investigations in the family were not possible, due to a lack of co-operation from family members. It is important to obtain a thorough and complete family history. When DNA-analysis remains inconclusive or if an unclassified variant is found, recommendations for surveillance will be based on this family history.

Reproductive genetic counseling for a familial genetic risk factor preferably takes place before conception. However, of the women with a family history of genetic conditions who attend our department of clinical genetics, about 10-20% attend for the first time during a pregnancy. The current study aims to explore patient-related factors that may affect this late timing of reproductive genetic counseling. Consecutive pregnant (n = 100) and non-pregnant (n = 84) women visiting the department of clinical genetics for a genetic risk factor which was not age related completed a questionnaire immediately prior to the consultation. The questionnaire asked for (a) background characteristics, i.e. socio-demographic, obstetric, and disease characteristics (b) cognitive factors, i.e. initiative of referral, knowledge of the risk factor involved, risk perception, worry, child wish, attitudes toward abortion, and preferred participation in decision making, and (c) reasons for the timing of the consultation and for seeking genetic counseling. Pregnant women appeared to be higher educated, considered their children more often as healthy and were less often affected themselves, as compared to non-pregnant women. They also estimated their chance of having an affected child as lower, and they worried less. Furthermore, the initiative for referral was taken less often by the pregnant woman herself and more often by a medical worker. There were no major differences between the two study groups in knowledge, perceived severity of the risk factor, child wish, attitudes toward abortion, desired participation in decision making, and reasons to seek genetic counseling. Women indicated no specific reasons for their timing of referral for reproductive genetic counseling, e.g. during vs before pregnancy. Our data suggest that this timing of referral is not influenced predominantly by the women's level of knowledge. Rather, women's estimation of genetic risks and their degree of worry, which may be in accordance with the actual risk figures, seem to play a role in seeking genetic counseling. Although further studies are required, a more active role of health care providers seems warranted if we want to prevent genetic counseling for familial genetic conditions during pregnancy as much as possible.

Three women aged 34, 23 and 39 years, who were respectively, 14, 12 and 8 weeks pregnant, requested genetic counselling due to grave genetic diseases in their families. The first woman chiefly wanted to be prepared; an investigation revealed no abnormalities and a healthy child was born. The second needed time to assimilate the information provided and terminated the pregnancy. For the third woman genetic screening was not possible in the short term and furthermore acceptation of the pregnancy was the biggest problem; she gave birth to a healthy child. In the Netherlands, about 800 to 1600 women every year request prenatal genetic counselling when they are already pregnant. The disadvantages of this late timing are the disquiet and uneasiness, the lost options and the time pressure under which difficult decisions have to be taken. Causes of this are a lack of genetic knowledge and psychosocial aspects. Ideally, genetic counselling that deals with reproductive issues should take place prior to conception.

Clinical, biochemical and molecular findings in a patient with methemoglobinemia type II are described. Furthermore, a comparison between methemoglobinemia type I and type II, both caused by a deficiency of NADH-cytochrome b5 reductase (b5R), is made. Although the clinical pictures of type I and II are strikingly different, mutations in the diaphorase (DIA1) gene located on chromosome 22 have been described in both types. In the present patient, two newly identified mutations, both leading to a stop codon in exon 4 (Gln77Ter) and in exon 6 (Arg160Ter), were found. Identification of different mutations at different positions in the DIA1 gene might shed light on the clinical and biochemical differences between methemoglobinemia type I and type II.

Hoyeraal-Hreidarsson (HH) syndrome is a multisystem disorder affecting boys characterized by aplastic anaemia (AA), immunodeficiency, microcephaly, cerebellar-hypoplasia and growth retardation. Its pathogenesis is unknown. X-linked dyskeratosis congenita (DC) is an inherited bone-marrow-failure syndrome characterized by skin pigmentation, nail dystrophy and leucoplakia which usually develop towards the end of the first decade of life. AA occurs in90% of cases of DC. We speculated that mutations in the gene responsible for X-linked DC (DKC1) may account for the HH syndrome, due to the phenotypic similarities between the disease in respect of AA and gender bias. We therefore analysed the DKC1 gene in two HH families. In one family a nucleotide change at position 361(A --G) in exon 5 was found in both affected brothers; in the other family a nucleotide change at position 146(C --T) in exon 3 was found in the affected boys. The finding of these two novel missense DKC1 mutations demonstrates that HH is a severe variant of DC. They also show that mutations in DKC1 can give rise to a very wide clinical spectrum of manifestations. Boys with unexplained AA or immunodeficiency should be tested for mutations in DKC1 even though they may lack diagnostic features of DC.

Three people applied for genetic counselling, but during the consultations the clinical geneticist discovered other problems for which advice could have been given but was not asked. This caused a serious dilemma. The first person was a woman who wanted to know the risks of epilepsy for her potential offspring, but then it became clear that she appeared to have Huntington's disease in the family. The second person was a man who wanted to know about the genetic risks for his offspring of a borderline psychiatric disorder, but the geneticist, seeing that the partner had severe limb defects, wondered whether these were caused by a genetic disorder. The third patient was a pregnant woman who came asking about the risks caused by mental retardation in one of her ancestors, but who appeared to be a heavy drinker and user of cocaine and ecstasy. In dealing with such 'secondary' problems, it should be kept in mind that persons seeking advice must decide for themselves whether or not they want to be informed regarding these problems or not.

We report on a girl with a duplication of chromosome band 11p12--13, which includes the Wilms tumor gene (WT1) and the aniridia gene (PAX6). The girl had borderline developmental delay, mild facial anomalies, and eye abnormalities. Eye findings were also present in most of the 11 other published cases with partial trisomy 11p, including 11p12--13. Recently, it was shown that introduction of additional copies of the PAX6 gene into mice caused very variable eye abnormalities. Therefore, a PAX6 gene dosage effect is likely to be present in mice and humans. The central nervous system may be less sensitive to an altered PAX6 gene dosage, which is consistent with the borderline developmental delay in the present patient. Urogenital abnormalities were absent in this patient and in most of the other patients with partial trisomy of 11p. Therefore, the effect of a WT1 gene duplication on the embryological development of the urogenital tract remains uncertain.

Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder that is phenotypically related to the Marfan syndrome. CCA has recently been shown to result from mutations in the FBN2 gene, which encodes an elastin-associated microfibrillar protein called fibrillin-2. Two siblings are reported here with classic manifestations of CCA with unaffected parents. Analysis of the FBN2 cDNA from dermal fibroblasts from one of the affected siblings revealed a heterozygous exon splicing error deleting nt 3722-3844 of the FBN2 mRNA. This cDNA deletion resulted in selective removal of one of the 43 calcium-binding EGF-like domains of the fibrillin-2 protein. Analysis of the FBN2 gene in the affected siblings' DNA indicated that the splicing error resulted from an A-to-G transition 15 nt upstream from the 3' splice site of the intron. The genomic mutation resulting in the splicing error alters a putative branch point sequence important for lariat formation, an intermediate structure of normal splicing. The mutation was detectable in DNA from the father's hair bulbs and buccal cells but not his white blood cell DNA, indicating that the father was a somatic mosaic. Analysis of transcript levels by use of dermal fibroblasts from the proband demonstrated that the FBN2 allele containing the exon deletion was expressed at a higher level than the allele inherited from the mother. These results indicate that FBN2 exon splicing errors are a cause of CCA, furthering the understanding of the molecular basis of this disorder. In addition, the demonstration of gonadal mosaicism in the FBN2 gene is important for accurate genetic counseling of families with sporadic cases of CCA. Finally, the preferential expression of the mutated FBN2 allele in dermal fibroblasts may have implications for understanding the pathogenesis and rarity of CCA.

In a male neonate dysmaturity, microcephalia, a high nasal bridge, a long philtrum, broad dental ridges, schisis of the palatum molle, retrognathia, a small penis with a chorda, a small scrotum, bilateral inguinal hernia and bilateral syndactyly of the second and third toes were observed. The presence of the Smith-Lemli-Opitz (SLO) syndrome was suspected. By gas chromatography a severely decreased plasma cholesterol level (0.27 mmol/l) was found and an increased plasma 7-dehydrocholesterol level (0.24 mmol/l). The SLO syndrome is caused by a block in the cholesterol biosynthesis due to the autosomal recessive deficiency of 7-dehydrocholesterol reductase. The patient's condition improved with use of a cholesterol-enriched diet.

A triad of acral, renal, and ocular abnormalities was reported previously in four families. We report on a fifth family, in which a mother, one of her four sons and one of her two daughters are affected. Major findings in the acro-renal-ocular syndrome are upper limb abnormalities, mainly thumb hypoplasia, eye abnormalities such as coloboma and Duane anomaly and renal migration defects. A close embryological-temporal relationship between the traits of this entity suggest a common monogenic cause. The pattern of inheritance is probably autosomal dominant. Because of a wide variability of clinical manifestations, recognition of the syndrome in individual cases may be difficult.

A triad of acral, renal, and ocular abnormalities was reported previously in four families. We report on a fifth family, in which a mother, one of her four sons and one of her two daughters are affected. Major findings in the acro-renal-ocular syndrome are upper limb abnormalities, mainly thumb hypoplasia, eye abnormalities such as coloboma and Duane anomaly and renal migration defects. A close embryological-temporal relationship between the traits of this entity suggest a common monogenic cause. The pattern of inheritance is probably autosomal dominant. Because of a wide variability of clinical manifestations, recognition of the syndrome in individual cases may be difficult.