Psychosocial Functioning in Transgender Youth after 2 Years of Hormones.

BACKGROUND: Limited prospective outcome data exist regarding transgender and nonbinary youth receiving gender-affirming hormones (GAH; testosterone or estradiol). METHODS: We characterized the longitudinal course of psychosocial functioning during the 2 years after GAH initiation in a prospective cohort of transgender and nonbinary youth in the United States. Participants were enrolled in a four-site prospective, observational study of physical and psychosocial outcomes. Participants completed the Transgender Congruence Scale, the Beck Depression Inventory-II, the Revised Children's Manifest Anxiety Scale (Second Edition), and the Positive Affect and Life Satisfaction measures from the NIH (National Institutes of Health) Toolbox Emotion Battery at baseline and at 6, 12, 18, and 24 months after GAH initiation. We used latent growth curve modeling to examine individual trajectories of appearance congruence, depression, anxiety, positive affect, and life satisfaction over a period of 2 years. We also examined how initial levels of and rates of change in appearance congruence correlated with those of each psychosocial outcome. RESULTS: A total of 315 transgender and nonbinary participants 12 to 20 years of age (mean [±SD], 16±1.9) were enrolled in the study. A total of 190 participants (60.3%) were transmasculine (i.e., persons designated female at birth who identify along the masculine spectrum), 185 (58.7%) were non-Latinx or non-Latine White, and 25 (7.9%) had received previous pubertal suppression treatment. During the study period, appearance congruence, positive affect, and life satisfaction increased, and depression and anxiety symptoms decreased. Increases in appearance congruence were associated with concurrent increases in positive affect and life satisfaction and decreases in depression and anxiety symptoms. The most common adverse event was suicidal ideation (in 11 participants [3.5%]); death by suicide occurred in 2 participants. CONCLUSIONS: In this 2-year study involving transgender and nonbinary youth, GAH improved appearance congruence and psychosocial functioning. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.).

Trajectories of illness uncertainty among parents of children with atypical genital appearance due to differences of sex development.

OBJECTIVE: The present study aimed to identify distinct trajectories of parental illness uncertainty among parents of children born with atypical genital appearance due to a difference of sex development over the first year following diagnosis. It was hypothesized that four trajectory classes would emerge, including "low stable," "high stable," "decreasing," and "increasing" classes, and that select demographic, familial, and medical factors would predict these classes. METHODS: Participants included 56 mothers and 43 fathers of 57 children born with moderate to severe genital atypia. Participants were recruited from eleven specialty clinics across the U.S. Growth mixture modeling (GMM) approaches, controlling for parent dyad clustering, were conducted to examine classes of parental illness uncertainty ratings over time. RESULTS: A three-class GMM was identified as the best-fitting model. The three classes were interpreted as "moderate stable" (56.8%), "low stable" (33.0%), and "declining" (10.3%). Findings suggest possible diagnostic differences across trajectories. CONCLUSIONS: Findings highlight the nature of parents' perceptions of ambiguity and uncertainty about their child's diagnosis and treatment the year following their child's birth/diagnosis. Future research is needed to better understand how these trajectories might shift over the course of the child's development. Results support the development of tailored, evidence-based interventions to address coping with uncertainty among families raising a child with chronic health needs.

Body image and psychosocial outcomes in youth and young adults with differences of sex development: a multi-method study.

OBJECTIVE: Differences of sex development (DSD) can affect the physical health, appearance, and psychosocial functioning of affected individuals, but little is known about how subjective appearance perceptions (body image) impact psychosocial outcomes. This study evaluated body image and its associations with psychosocial outcomes including quality of life, resilience, and psychosocial adjustment. METHODS: This cross-sectional, multi-method study assessed body image and psychosocial outcomes including quality of life, adjustment, and resilience in 97 youth and young adults with DSD (mean age = 17 ± 3.7 years; 56% assigned female in infancy) using psychometrically sound instruments. A subsample (n = 40) completed qualitative interviews. RESULTS: Quantitative results indicated that overall, participants were satisfied with their physical appearance, although less so with their primary sex characteristics. Body image dissatisfaction was associated with poorer psychosocial adjustment, quality of life, and resilience. Qualitatively, youth and young adults reported a variety of perceptions, both positive and negative, related to their body image and the impact of living with a DSD condition. Themes identified included appearance management; effects of DSD on body image; diagnostic factors and features; attitudes about diagnosis; and treatment. CONCLUSIONS: Body image is significantly associated with psychosocial outcomes in youth and young adults with DSD, with qualitative findings highlighting both positive and negative body image experiences. Results have implications for clinical care including screening for appearance concerns, normalization of appearance variations, and intervention development to better support healthy body image and psychosocial functioning in youth and young adults with DSD.

Adverse Birth Experiences and Parent Adjustment Associated With Atypical Genital Appearance Due to Differences of Sex Development.

OBJECTIVE: Differences/disorders of sex development (DSDs) are rare, congenital conditions involving discordance between chromosomes, gonads, and phenotypic sex and are often diagnosed in infancy. A key subset of parents of children newly diagnosed with a DSD experience clinically elevated distress. The present study examines the relationship between perinatal factors (i.e., gestational age, delivery method) and trajectories of parental adjustment. METHODS: Parent participants (mothers = 37; fathers = 27) completed measures at baseline, 6- and 12-month follow-up. Multilevel linear regression controlled for clustering of the data at three levels (i.e., time point, parent, and family) and examined the relationship between perinatal factors and trajectories of depressive and anxious symptoms. Two-way interactions between perinatal factors and parent type were evaluated. RESULTS: Overall depressive and anxious symptoms decreased over time. There were significant interactions between gestational age and parent type for depressive and anxious symptoms, with younger gestational age having a stronger negative effect on mothers vs. fathers. There was a significant interaction between time and gestational age for depressive symptoms, with 36 weeks' gestational age demonstrating a higher overall trajectory of depressive symptoms across time compared to 38 and 40 weeks. Findings for the delivery method were not significant. CONCLUSIONS: Findings uniquely demonstrated younger gestational age was associated with increased depressive symptoms, particularly for mothers compared to fathers. Thus, a more premature birth may predispose parents of infants with DSD to distress. Psychosocial providers should contextualize early diagnosis-related discussions within stressful birth experiences when providing support.

TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci.

Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated GnRH deficiency (IGD). Here, we report 13 families (12 autosomal dominant and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome) with loss-of-function mutations in TCF12, a locus also known to cause syndromic and non-syndromic craniosynostosis. We show that loss of tcf12 in zebrafish larvae perturbs GnRH neuronal patterning with concomitant attenuation of the orthologous expression of tcf3a/b, encoding a binding partner of TCF12, and stub1, a gene that is both mutated in other syndromic forms of IGD and maps to a TCF12 affinity network. Finally, we report that restored STUB1 mRNA rescues loss of tcf12 in vivo. Our data extend the mutational landscape of IGD, highlight the genetic links between craniofacial patterning and GnRH dysfunction and begin to assemble the functional network that regulates the development of the GnRH axis.

The effect of gender-affirming hormone treatment on serum creatinine in transgender and gender-diverse youth: implications for estimating GFR.

BACKGROUND: Equations for estimated glomerular filtration rate (eGFR) based on serum creatinine include terms for sex/gender. For transgender and gender-diverse (TGD) youth, gender-affirming hormone (GAH) treatment may affect serum creatinine and in turn eGFR. METHODS: TGD youth were recruited for this prospective, longitudinal, observational study prior to starting GAH treatment. Data collected as part of routine clinical care were abstracted from the medical record. RESULTS: For participants designated male at birth (DMAB, N = 92), serum creatinine decreased within 6 months of estradiol treatment (mean ± SD 0.83 ± 0.12 mg/dL to 0.76 ± 0.12 mg/dL, p < 0.001); for participants designated female at birth (DFAB, n = 194), serum creatinine increased within 6 months of testosterone treatment (0.68 ± 0.10 mg/dL to 0.79 ± 0.11 mg/dL, p < 0.001). Participants DFAB treated with testosterone had serum creatinine similar to that of participants DMAB at baseline, whereas even after estradiol treatment, serum creatinine in participants DMAB remained higher than that of participants DFAB at baseline. Compared to reference groups drawn from the National Health and Nutritional Examination Survey, serum creatinine after 12 months of GAH was more similar when compared by gender identity than by designated sex. CONCLUSION: GAH treatment leads to changes in serum creatinine within 6 months of treatment. Clinicians should consider a patient's hormonal exposure when estimating kidney function via eGFR and use other methods to estimate GFR if eGFR based on serum creatinine is concerning.

Burden Testing of Rare Variants Identified through Exome Sequencing via Publicly Available Control Data.

The genetic causes of many Mendelian disorders remain undefined. Factors such as lack of large multiplex families, locus heterogeneity, and incomplete penetrance hamper these efforts for many disorders. Previous work suggests that gene-based burden testing-where the aggregate burden of rare, protein-altering variants in each gene is compared between case and control subjects-might overcome some of these limitations. The increasing availability of large-scale public sequencing databases such as Genome Aggregation Database (gnomAD) can enable burden testing using these databases as controls, obviating the need for additional control sequencing for each study. However, there exist various challenges with using public databases as controls, including lack of individual-level data, differences in ancestry, and differences in sequencing platforms and data processing. To illustrate the approach of using public data as controls, we analyzed whole-exome sequencing data from 393 individuals with idiopathic hypogonadotropic hypogonadism (IHH), a rare disorder with significant locus heterogeneity and incomplete penetrance against control subjects from gnomAD (n = 123,136). We leveraged presumably benign synonymous variants to calibrate our approach. Through iterative analyses, we systematically addressed and overcame various sources of artifact that can arise when using public control data. In particular, we introduce an approach for highly adaptable variant quality filtering that leads to well-calibrated results. Our approach "re-discovered" genes previously implicated in IHH (FGFR1, TACR3, GNRHR). Furthermore, we identified a significant burden in TYRO3, a gene implicated in hypogonadotropic hypogonadism in mice. Finally, we developed a user-friendly software package TRAPD (Test Rare vAriants with Public Data) for performing gene-based burden testing against public databases.

Psychosocial Functioning Among Children With and Without Differences of Sex Development.

OBJECTIVE: To assess health-related quality of life (HRQoL), psychosocial adjustment, and family functioning of children with differences of sex development (DSD) or cleft lip and/or palate (CL/P). METHODS: In this cross-sectional study, parents of children with DSD (n = 67), CL/P (n = 121), and a comparison group of unaffected youth (n = 126) completed standardized measures assessing family functioning and their children's HRQoL and psychosocial adjustment. Medical charts were abstracted for youth with either congenital condition. RESULTS: Children with DSD were rated as having significantly lower HRQoL and greater internalizing problems compared to youth with CL/P and unaffected youth. Children in the DSD group were also significantly more likely to fall into the clinical risk categories for total and internalizing problems relative to the CL/P and unaffected groups. Caregivers of children with DSD were significantly more likely to endorse items about child suicidality compared with caregivers in the CL/P and unaffected groups. No significant differences were found between groups for externalizing problems or the expressiveness domain of family functioning; parents of children with DSD reported significantly less family conflict relative to the other groups and greater cohesion relative to the unaffected group. Conclusions Youth with DSD appear to be at greater risk for psychosocial problems relative to children with CL/P and unaffected peers. Results underscore the need for integrated interdisciplinary care and ongoing psychosocial risk monitoring in youth with DSD.

Distress Trajectories for Parents of Children With DSD: A Growth Mixture Model.

OBJECTIVE: This study identifies trajectories of parent depressive symptoms after having a child born with genital atypia due to a disorder/difference of sex development (DSD) or congenital adrenal hyperplasia (CAH) and across the first year postgenitoplasty (for parents who opted for surgery) or postbaseline (for parents who elected against surgery for their child). Hypotheses for four trajectory classes were guided by parent distress patterns previously identified among other medical conditions. METHODS: Participants included 70 mothers and 50 fathers of 71 children diagnosed with a DSD or CAH with reported moderate to high genital atypia. Parents were recruited from 11 US DSD specialty clinics within 2 years of the child's birth and prior to genitoplasty. A growth mixture model (GMM) was conducted to identify classes of parent depressive symptoms over time. RESULTS: The best fitting model was a five-class linear GMM with freely estimated intercept variance. The classes identified were termed "Resilient," "Recovery," "Chronic," "Escalating," and "Elevated Partial Recovery." Four classes have previously been identified for other pediatric illnesses; however, a fifth class was also identified. The majority of parents were classified in the "Resilient" class (67.6%). CONCLUSIONS: This study provides new knowledge about the trajectories of depressive symptoms for parents of children with DSD. Future studies are needed to identify developmental, medical, or familial predictors of these trajectories.

Illness Uncertainty Longitudinally Predicts Distress Among Caregivers of Children Born With DSD.

OBJECTIVE: A subset of parents of children with disorders/differences of sex development (DSD) including ambiguous genitalia experience clinically elevated levels of anxious and depressive symptoms. Research indicates that uncertainty about their child's DSD is associated with parent psychosocial distress; however, previous studies have been cross-sectional or correlational in nature. The current study is the first to examine the longitudinal trajectory of the relationship between caregiver-perceived uncertainty about their child's DSD and caregiver anxious and depressive symptoms across the first 12 months following genital surgery in young children, or if surgery was not performed, the first 12 months following study entry. METHODS: One hundred and thirteen caregivers (Mage = 32.12; 57.5% mothers; 72.6% Caucasian) of children (N = 70; Mage = 9.81 months; 65.7% female) with DSD were recruited from 12 DSD specialty clinics in the United States. Caregivers completed psychosocial measures at baseline, 6 and 12 months following genitoplasty, or study entry if parents elected not to have surgery for their child. RESULTS: Caregiver illness uncertainty and both anxious and depressive symptoms were highest at baseline and decreased over time (ps < .05). Caregiver illness uncertainty predicted symptoms of anxious and depressive symptoms across all time points (ps < .05). CONCLUSIONS: Caregivers' perceptions of uncertainty about their child's DSD are highest soon after diagnosis, and uncertainty continues to predict both anxious and depressive symptoms across time. Thus, the initial diagnostic period is a critical time for psychological assessment and intervention, with parent illness uncertainty being an important clinical target.

PRACTICE VARIATION IN THE MANAGEMENT OF GIRLS AND BOYS WITH DELAYED PUBERTY.

Objective: Delayed puberty is a common condition, and typical management includes "watchful waiting" and/or sex-steroid therapy. We sought to characterize treatment practices and to assess provider comfort with the management of delayed puberty in girls and boys. Methods: A national survey of pediatric endocrine providers assessed definitions of delayed puberty, practices around sex-steroid therapy, reasons for treatment, and comfort in managing delayed puberty in girls and boys. Results: Of 184 respondents (12% participation rate), 64% and 71% used the traditional age cutoffs for defining delayed puberty of 13 years for girls and 14 years for boys, respectively. Nearly half (45%) of providers would treat boys relatively earlier than girls, compared to 18% who would treat girls relatively earlier (P<.0001). Providers were more likely to cite bone density as a reason to treat girls and alleviating patient and parental distress, accelerating growth, and "jump starting" puberty as reasons to treat boys. Greater experience in endocrine practice was associated with greater comfort managing delayed puberty in both boys and girls. Approximately 80% of providers agreed that clinical guidelines are needed for the management of delayed puberty. Conclusion: There is a high degree of variability in the clinical management of delayed puberty, and our results suggest that providers are more hesitant to treat girls compared to boys and have different reasons for treating each. It remains to be determined if these discrepancies in treatment are justified by biologic differences between girls and boys or represent nonevidence-based disparities in care. Abbreviation: U.S. = United States.

Determinants of Power in Gene-Based Burden Testing for Monogenic Disorders.

Whole-exome sequencing has enabled new approaches for discovering genes associated with monogenic disorders. One such approach is gene-based burden testing, in which the aggregate frequency of "qualifying variants" is compared between case and control subjects for each gene. Despite substantial successes of this approach, the genetic causes for many monogenic disorders remain unknown or only partially known. It is possible that particular genetic architectures lower rates of discovery, but the influence of these factors on power has not been rigorously evaluated. Here, we leverage large-scale exome-sequencing data to create an empirically based simulation framework to evaluate the impact of key parameters (background variation rates, locus heterogeneity, mode of inheritance, penetrance) on power in gene-based burden tests in the context of monogenic disorders. Our results demonstrate that across genes, there is a wide range in sample sizes needed to achieve power due to differences in the background rate of rare variants in each gene. Increasing locus heterogeneity results in rapid increases in sample sizes needed to achieve adequate power, particularly when individual genes contribute to less than 5% of cases under a dominant model. Interestingly, incomplete penetrance as low as 10% had little effect on power due to the low prevalence of monogenic disorders. Our results suggest that moderate incomplete penetrance is not an obstacle in this gene-based burden testing approach but that dominant disorders with high locus heterogeneity will require large sample sizes. Our simulations also provide guidance on sample size needs and inform study design under various genetic architectures.

Predictors of Psychosocial Distress in Parents of Young Children with Disorders of Sex Development.

PURPOSE: We evaluated demographic, financial and support predictors of distress for parents of young children with disorders of sex development including atypical genital development, and characterized early parental experiences. This work extends our previous findings to identify those parents at risk for distress. MATERIALS AND METHODS: Participants included mothers (76) and fathers (63) of a child (78) diagnosed with disorders of sex development characterized by moderate to severe genital atypia. Parents completed a demographic questionnaire, measures of anxious and depressive symptoms, quality of life, illness uncertainty and posttraumatic stress symptoms, and rated their satisfaction with the appearance of their child's genitalia. RESULTS: Depressive and posttraumatic stress symptoms of caregivers were comparable to standardized norms while levels of anxious symptoms were below norms. A subset of parents reported clinically elevated symptoms. Overall 26% of parents reported anxious symptoms, 24% reported depressive symptoms and 17% reported posttraumatic stress symptoms. Levels of illness uncertainty were lower than those of parents of children with other chronic illnesses. Differences by parent sex emerged, with mothers reporting greater distress. Lower income, increased medical care and travel expenses, and having no other children were related to increased psychosocial distress. CONCLUSIONS: Early psychosocial screening is recommended for parents of children with disorders of sex development. Clinicians should be aware that financial burden and lack of previous parenting experience are risk factors for distress.

Uncertainty and Posttraumatic Stress: Differences Between Mothers and Fathers of Infants with Disorders of Sex Development.

Parents of children with disorders of sex development (DSD) report significant psychological distress, including posttraumatic stress symptoms (PTSS), with mothers consistently reporting higher rates of psychological distress than fathers. However, psychological factors contributing to PTSS in both parents are not well understood. The present study sought to fill this gap in knowledge by examining PTSS and illness uncertainty, a known predictor of psychological distress, in parents of children recently diagnosed with DSD. Participants were 52 mothers (Mage = 32.55 years, SD = 5.08) and 41 fathers (Mage = 35.53 years, SD = 6.78) of 53 infants (Mage = 9.09 months, SD = 6.19) with DSD and associated atypical genital development. Participants were recruited as part of a larger, multisite study assessing parents' psychosocial response to their child's diagnosis of DSD. Parents completed measures of illness uncertainty and PTSS. Mothers reported significantly greater levels of PTSS, but not illness uncertainty, than fathers, and were more likely than fathers to report clinical levels of PTSS (21.2% compared to 7.3%). Hierarchical regression revealed that parent sex, undiagnosed or unclassified DSD status, and illness uncertainty were each associated with PTSS. The overall model accounted for 23.5% of the variance associated with PTSS. Interventions targeting illness uncertainty may be beneficial for parents of children with newly diagnosed DSD.

TESTICULAR REGRESSION SYNDROME: PRACTICE VARIATION IN DIAGNOSIS AND MANAGEMENT.

Objective: The purpose of this study was to assess clinical practice patterns with regard to diagnosis and management of testicular regression syndrome (TRS), a condition in 46,XY males with male phenotypic genitalia and bilateral absence of testes. Methods: A retrospective review was conducted at two large pediatric academic centers to examine diagnostic and management approaches for TRS. Results: Records of 57 patients were reviewed. Diagnostic methods varied widely between patients and included hormonal testing, karyotype, imaging, and surgical exploration, with multiple diagnostic methods frequently used in each patient. Of the 30 subjects that had reached adolescence at the time of the study, 17 (57%) had gaps in care of more than 5 years during childhood. Thirty subjects had received testosterone replacement therapy at a mean age of 12.1 ± 1.0 years. Forty-seven percent had a documented discussion of infertility. Eighty-two percent discussed prosthesis placement, with 35% having prostheses placed. Twenty-three percent were seen by a psychosocial provider. The between-site differences were age at fertility discussion, age at and number of prostheses placed, and type/age of testosterone initiation. Conclusion: Our findings highlight the wide variation in diagnostic approaches, follow-up frequency, testosterone initiation, fertility counseling, and psychosocial support for patients with TRS. Developing evidence-based guidelines for the evaluation and management of TRS would help reduce inconsistencies in care and unnecessary testing. Ongoing follow-up and coordination of care, even during the years when no hormonal treatment is being administered, could lead to opportunities for psychosocial support and improved interdisciplinary approach to care. Abbreviations: AMH = antimüllerian hormone; CAH = congenital adrenal hyperplasia; DSD = differences/disorders of sex development; hCG = human chorionic gonadotropin; TRS = testicular regression syndrome.

The Biological Contributions to Gender Identity and Gender Diversity: Bringing Data to the Table.

The American Psychological Association defines gender identity as, "A person's deeply-felt, inherent sense of being a boy, a man, or a male; a girl, a woman, or a female; or an alternative gender (e.g., genderqueer, gender nonconforming, gender neutral) that may or may not correspond to a person's sex assigned at birth or to a person's primary or secondary sex characteristics" (American Psychological Association, Am Psychol 70(9):832-864, 2015). Here we review the evidence that gender identity and related socially defined gender constructs are influenced in part by innate factors including genes. Based on the data reviewed, we hypothesize that gender identity is a multifactorial complex trait with a heritable polygenic component. We argue that increasing the awareness of the biological diversity underlying gender identity development is relevant to all domains of social, medical, and neuroscience research and foundational for reducing health disparities and promoting human-rights protections for gender minorities.

Genetics of pubertal timing.

PURPOSE OF REVIEW: To summarize advances in the genetics underlying variation in normal pubertal timing, precocious puberty, and delayed puberty, and to discuss mechanisms by which genes may regulate pubertal timing. RECENT FINDINGS: Genome-wide association studies have identified hundreds of loci that affect pubertal timing in the general population in both sexes and across ethnic groups. Single genes have been implicated in both precocious and delayed puberty. Potential mechanisms for how these genetic loci influence pubertal timing may include effects on the development and function of the GnRH neuronal network and the responsiveness of end-organs. SUMMARY: There has been significant progress in identifying genetic loci that affect normal pubertal timing, and the first single-gene causes of precocious and delayed puberty are being described. How these genes influence pubertal timing remains to be determined.

Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies.

BACKGROUND: A constellation of neurodegenerative disorders exists (Gordon Holmes syndrome, 4H leucodystrophy, Boucher-Neuhauser syndrome) in which patients suffer from both neurological disease (typically manifested by ataxia) and reproductive failure (idiopathic hypogonadotropic hypogonadism (IHH)). POLR3B, which encodes the second largest subunit of RNA polymerase III (pol III), and POLR3A, which forms the pol III catalytic centre, are associated with 4H leucodystrophy. METHODS: Whole exome sequencing was performed on a large cohort of subjects with IHH (n=565). Detailed neuroendocrine studies were performed in some individuals within this cohort. RESULTS: Four individuals (two of them siblings) were identified with two rare nucleotide variants in POLR3B. On initial evaluation, all subjects were free of neurological disease. One patient underwent treatment with exogenous pulsatile gonadotropin-releasing hormone for 8 weeks which failed to result in normalisation of his sex steroid milieu due to pituitary resistance. CONCLUSIONS: These findings suggest that the spectrum of phenotypes resulting from POLR3B mutations is wider than previously believed and that POLR3B can be associated exclusively with disorders characterised by abnormal gonadotropin secretion.

Recent findings on the genetics of disorders of sex development.

PURPOSE OF REVIEW: Disorders of sex development (DSD) are a diverse group of conditions affecting gonadal development, sexual differentiation, or chromosomal sex. In this review, we will discuss recent literature on the genetic causes of DSD, with a focus on novel genetic sequencing technologies, new phenotypes associated with known DSD genes, and increasing recognition of the role of genetic regulatory elements in DSD. RECENT FINDINGS: We performed a comprehensive search of PubMed through August 2016 to identify important peer-reviewed publications from 2015 to 2016 on the topic of DSD genetics. SUMMARY: Whole-exome sequencing was used to successfully identify genetic causes of DSD in 35% of a cohort of 46,XY patients who had not previously received a genetic diagnosis. A novel mutation in NR5A1 has been identified as a cause of 46,XX testicular and ovotesticular DSD, demonstrating a previously unappreciated role of NR5A1 in preventing testicular differentiation in 46,XX individuals. Genetic regulatory elements of SOX9 have been identified as causes of 46,XX and 46,XY DSD.