Update on the predictability of tall stature from DNA markers in Europeans.

Predicting adult height from DNA has important implications in forensic DNA phenotyping. In 2014, we introduced a prediction model consisting of 180 height-associated SNPs based on data from 10,361 Northwestern Europeans enriched with tall individuals (770 > 1.88 standard deviation), which yielded a mid-ranged accuracy (AUC = 0.75 for binary prediction of tall stature and R2 = 0.12 for quantitative prediction of adult height). Here, we provide an update on DNA-based height predictability considering an enlarged list of subsequently-published height-associated SNPs using data from the same set of 10,361 Europeans. A prediction model based on the full set of 689 SNPs showed an improved accuracy relative to previous models for both tall stature (AUC = 0.79) and quantitative height (R2 = 0.21). A feature selection analysis revealed a subset of 412 most informative SNPs while the corresponding prediction model retained most of the accuracy (AUC = 0.76 and R2 = 0.19) achieved with the full model. Over all, our study empirically exemplifies that the accuracy for predicting human appearance phenotypes with very complex underlying genetic architectures, such as adult height, can be improved by increasing the number of phenotype-associated DNA variants. Our work also demonstrates that a careful sub-selection allows for a considerable reduction of the number of DNA predictors that achieve similar prediction accuracy as provided by the full set. This is forensically relevant due to restrictions in the number of SNPs simultaneously analyzable with forensically suitable DNA technologies in the current days of targeted massively parallel sequencing in forensic genetics

Prevalence of c-KIT mutations in gonadoblastoma and dysgerminomas of patients with disorders of sex development (DSD) and ovarian dysgerminomas

Activating c-KIT mutations (exons 11 and 17) are found in 10-40% of testicular seminomas, the majority being missense point mutations (codon 816). Malignant ovarian dysgerminomas represent similar to 3% of all ovarian cancers in Western countries, resembling testicular seminomas, regarding chromosomal aberrations and c-KIT mutations. DSD patients with specific Y-sequences have an increased risk for Type II Germ Cell Tumor/Cancer, with gonadoblastoma as precursor progressing to dysgerminoma. Here we present analysis of c-KIT exon 8, 9, 11, 13 and 17, and PDGFRA exon 12, 14 and 18 by conventional sequencing together with mutational analysis of c-KIT codon 816 by a sensitive and specific LightCycler melting curve analysis, confirmed by sequencing. The results are combined with data on TSPY and OCT3/4 expression in a series of 16 DSD patients presenting with gonadoblastoma and dysgerminoma and 15 patients presenting pure ovarian dysgerminomas without DSD. c-KIT codon 816 mutations were detected in five out of the total of 31 cases (all found in pure ovarian dysgerminomas). A synonymous SNP (rs 5578615) was detected in two patients, one DSD patient (with bilateral disease) and one patient with dysgerminoma. Next to these, three codon N822K mutations were detected in the group of 15 pure ovarian dysgerminomas. In total activating c-KIT mutations were found in 53% of ovarian dysgerminomas without DSD. In the group of 16 DSD cases a N505I and D820E mutation was found in a single tumor of a patient with gonadoblastoma and dysgerminoma. No PDGFRA mutations were found. Positive OCT3/4 staining was present in all gonadoblastomas and dysgerminomas investigated, TSPY expression was only seen in the gonadoblastoma/dysgerminoma lesions of the 16 DSD patients. This data supports the existence of two distinct but parallel pathways in the development of dysgerminoma, in which mutational status of c-KIT might parallel the presence of TSPY

Update on the predictability of tall stature from DNA markers in Europeans.

Predicting adult height from DNA has important implications in forensic DNA phenotyping. In 2014, we introduced a prediction model consisting of 180 height-associated SNPs based on data from 10,361 Northwestern Europeans enriched with tall individuals (770 > 1.88 standard deviation), which yielded a mid-ranged accuracy (AUC = 0.75 for binary prediction of tall stature and R2 = 0.12 for quantitative prediction of adult height). Here, we provide an update on DNA-based height predictability considering an enlarged list of subsequently-published height-associated SNPs using data from the same set of 10,361 Europeans. A prediction model based on the full set of 689 SNPs showed an improved accuracy relative to previous models for both tall stature (AUC = 0.79) and quantitative height (R2 = 0.21). A feature selection analysis revealed a subset of 412 most informative SNPs while the corresponding prediction model retained most of the accuracy (AUC = 0.76 and R2 = 0.19) achieved with the full model. Over all, our study empirically exemplifies that the accuracy for predicting human appearance phenotypes with very complex underlying genetic architectures, such as adult height, can be improved by increasing the number of phenotype-associated DNA variants. Our work also demonstrates that a careful sub-selection allows for a considerable reduction of the number of DNA predictors that achieve similar prediction accuracy as provided by the full set. This is forensically relevant due to restrictions in the number of SNPs simultaneously analyzable with forensically suitable DNA technologies in the current days of targeted massively parallel sequencing in forensic genetics

Recalled and current gender role behavior, gender identity and sexual orientation in adults with Disorders/Differences of Sex Development

The magnitude of sex differences in human brain and behavior and the respective contributions of biology versus socialization remain a topic of ongoing study in science. The preponderance of evidence attests to the notion that sexual differentiation processes are at least partially hormonally mediated, with high levels of prenatal androgens facilitating male-typed and inhibiting female-typed behaviors. In individuals with Disorders/Differences of Sex Development (DSD), hormonal profiles or sensitivities have been altered due to genetic influences, presumably affecting gender(ed) activity interests as well as gender identity development in a minority of the affected population. While continued postnatal androgen exposure in a number of DSD syndromes has been associated with higher rates of gender dysphoria and gender change, the role of a number of mediating and moderating factors, such as initial gender assignment, syndrome severity and clinical management remains largely unclear. Limited investigations of the associations between these identified influences and gendered development outcomes impede optimization of clinical care. Participants with DSD (n = 123), recruited in the context of a Dutch multi-center follow-up audit, were divided in subgroups reflecting prenatal androgen exposure, genital appearance at birth and gender of rearing. Recalled childhood play and playmate preferences, gender identity and sexual orientation were measured with questionnaires and semi-structured interviews. Data were compared to those of control male (n = 46) and female participants (n = 79). The findings support that (a) prenatal androgen exposure has large effects on (gendered) activity interests, but to a much lesser extent on sexual orientation and that (b) initial gender of rearing remains a better predictor of gender identity contentedness than prenatal androgen exposure, beyond syndrome severity and medical treatment influences. Nonetheless, 3.3% of individuals with DSD in our sample self-reported gender dysphoria from an early age and changed gender, which further underlines the need for thorough long- term follow-up and specific clinical support

Long-term outcomes in males with disorders of sex development

Purpose: Indications that the prenatal action of testosterone in the brain is an important determinant of gender development and improved reconstructive techniques have caused a shift in male gender assignments in patients with 46XY disorders of sex development. We report long-term outcome data on psychosexual development and sexual function of these individuals in a cross-sectional study. Materials and Methods: Physical status of 14 men with a mean age of 25 years with disorders of sex development was assessed by structured interview and physical examination. Psychosexual outcome was evaluated by questionnaires and compared to a control group of 46 healthy, age matched men. Results: A total of 13 men underwent 1 to 6 (mean 2) genital surgeries. Mean age at first surgery was 2.7 years. Mean penile length was 6.6 cm. All men reported erections and were able to experience orgasms. Ejaculatory dysfunction was reported by 7 men. Mean penile length was 7.9 cm in patients who were able to achieve penetrative intercourse and 4.9 cm in those who were not. Meatus was glanular in 5 patients, coronal in 7 and at the distal shaft in 1. Compared to controls, men with disorders of sex development were less satisfied with the appearance of the penis and scrotum but not with total body image. These patients reported decreased sexual desire and activities. Conclusions: Outcome in this group of men with disorders of sex development was poor regarding penile length, ejaculation, satisfaction with external genitalia and frequency of sexual activity. Other aspects, such as overall body image and psychosexual functioning, showed no difference from controls

Psychosocial well-being in Dutch adults with disorders of sex development

Objective: Atypical sex development is associated with psychosocial vulnerability. We investigated psychosocial well-being in individuals with disorders of sex development (DSD) and hypothesized that psychosocial well-being was related to degree of genital atypicality at birth. Methods: 120 male (n = 16) and female (n = 104) persons with DSD, aged 14-60 years, participated in a follow-up audit on psychosocial well-being. They were stratified in: women with 1) 46,XY and female genitalia, 2) 46,XY or 46,XX and atypical genitalia, and 3) men with 46,XY and atypical genitalia. We used the Illness Cognition Questionnaire (ICQ), Checklist Individual Strength (CIS8R), TNO-AZL Quality of Life questionnaire (TAAQOL), Adult Self-Report (ASR), and the Rosenberg Self-Esteem Scale (RSES). Results: Data were compared to reference groups. Participants generally were coping well with DSD (ICQ). Women with DSD reported elevated levels of fatigue (CIS8R) and slightly more attention and memory problems (TAAQOL, ASR). Women with atypical genitalia reported more emotional and behavioral problems. On the ASR Rule-breaking Behavior and Antisocial Personality scales, these women had similar scores as reference men. Women with DSD reported a higher self-esteem (RSES). No differences in psychosocial well-being were found between men with DSD and reference men. Conclusion: Individuals with DSD across all diagnostic groups generally reported a good psychosocial well-being. The results further suggest involvement of prenatal androgens in the development of personality traits related to assertiveness and egocentricity. We recommend that individuals with a DSD and their families are involved in decision-making processes and have access to multidisciplinary care

Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology

Patients with complete androgen insensitivity syndrome are at an increased risk for the development of gonadal germ cell cancer. Residual androgen receptor (AR) activity and abnormal gonadal location may influence the survival of atypical germ cells and the development of other histopathological features. To assess this, we evaluated 37 gonads from 19 patients with complete androgen insensitivity (ranging in age from 3 months to 18 years). Histological abnormalities were examined using hematoxylin and eosin-stained sections and sections stained for POU5F1 and KITLG, markers of early changes in germ cells at risk for malignant transformation. Hamartomatous nodules (HNs), Leydig cell hyperplasia (LCH), decreased germ cells, tubular atrophy and stromal fibrosis were more pronounced as age increased (P<0.001). Expected residual AR activity acted as a positive predictor only for non-malignant germ cell survival in (post)pubertal patients (P<0.05). Immunohistochemical studies indicated that delayed maturation of germ cells was present in three patients, whereas intermediate changes that occurred between delayed maturation and intratubular germ cell neoplasia, designated pre-intratubular germ cell neoplasia, were identified in four cases. Intratubular germ cell neoplasia was observed in one patient. Neither POU5F1 nor KITLG expression was dependent on expected residual AR activity. An independent effect of inguinal versus abdominal position of the gonads was difficult to assess because inguinal gonads were present primarily in the youngest individuals. In conclusion, many histological changes occur increasingly with age. Expected residual AR activity contributes to better survival of the general germ cell population in (post)pubertal age; however, it did not seem to have an important role in the survival of the germ cells at risk for malignant transformation (defined by POU5F1 positivity and KITLG overexpression) in complete androgen insensitivity. Comparison of the high percentage of patients in our study that were carrying germ cells with delayed maturation or pre-intratubular germ cell neoplasia with previously reported cumulative risk of tumor development in adult patients indicates that not all such precursor lesions in complete androgen insensitivity will progress to invasive germ cell cancer

Gonadal malignancy in 13 consecutive collected patients with disorders of sex development (DSD) from Semarang (Indonesia)

Aims : Caucasian patients with disorders of sex development (DSD) are at a high risk of developing germ cell cancer (GCC). GCC is prominent in young adults in Western countries, while the incidence is significantly lower in Asia. So far, the risk of GCC in Asian DSD patients is unknown. Methods and results : A detailed study of gonad histology, morphology and immunohistochemistry (OCT3/4, testis-specific protein Y-encoded, VASA, SCF/KITLG, SOX9, FOXL2) of 16 Indonesian DSD patients was undertaken. 13 cases could be analysed, including ovarian tissue (n=3), streak gonad (n=1), undifferentiated gonad (n=1) and testicular tissue (n=8), diagnosed as 46, XX (n=1), 46, XY (n=7) and sex chromosome DSD (n=5). The precursor lesion gonadoblastoma or carcinoma in situ, or GCC was diagnosed in four cases (30.8%; three 46, XY and one sex chromosome DSD). A hormone producing ovarian Leydig cell tumour was identified in a 46, XX patient, supposed to be a late onset congenital adrenal hyperplasia. Conclusions : In spite of the significantly lower risk of GCC in the general Asian population, DSD is a dominant risk factor. The study demonstrates the power of immunohistochemical markers for (early) diagnosis. This knowledge will deepen understanding of the pathobiology of GCC and clinical handling of patients with DSD, globally

<it>SRY</it> mutation analysis by next generation (deep) sequencing in a cohort of chromosomal Disorders of Sex Development (DSD) patients with a mosaic karyotype

<p>Abstract</p> <p>Background</p> <p>The presence of the Y-chromosome or Y chromosome-derived material is seen in 4-60% of Turner syndrome patients (Chromosomal Disorders of Sex Development (DSD)). DSD patients with specific Y-chromosomal material in their karyotype, the GonadoBlastoma on the Y-chromosome (GBY) region, have an increased risk of developing type II germ cell tumors/cancer (GCC), most likely related to TSPY. The Sex determining Region on the Y gene (<it>SRY</it>) is located on the short arm of the Y-chromosome and is the crucial switch that initiates testis determination and subsequent male development. Mutations in this gene are responsible for sex reversal in approximately 10-15% of 46,XY pure gonadal dysgenesis (46,XY DSD) cases. The majority of the mutations described are located in the central HMG domain, which is involved in the binding and bending of the DNA and harbors two nuclear localization signals. <it>SRY</it> mutations have also been found in a small number of patients with a 45,X/46,XY karyotype and might play a role in the maldevelopment of the gonads.</p> <p>Methods</p> <p>To thoroughly investigate the presence of possible <it>SRY</it> gene mutations in mosaic DSD patients, we performed next generation (deep) sequencing on the genomic DNA of fourteen independent patients (twelve 45,X/46,XY, one 45,X/46,XX/46,XY, and one 46,XX/46,XY).</p> <p>Results and conclusions</p> <p>The results demonstrate that aberrations in <it>SRY</it> are rare in mosaic DSD patients and therefore do not play a significant role in the etiology of the disease.</p