Unusual suspects in hereditary melanoma: POT1, POLE, BAP1.

Systematic literature searches on POT1/POLE/BAP1 found that limited skin phenotypic characteristics have been documented in mutation carriers; 248 variants were annotated, and high-cluster variant regions associated with cutaneous melanoma were found in all three genes. Genotype-phenotype correlations can be used to identify patient disease predisposition based on mutation position and cluster regions.

POT1 and multiple primary melanomas: the dermatological phenotype.

POT1 is the second most frequently reported gene (after CDKN2A) in familial melanoma. Pathogenic variants are associated with earlier onset and/or multiple primary melanomas (MPMs). To date, POT1 phenotypical reports have been largely restricted to associated malignancies, and description of the dermatological landscape has been limited. We identified 10 variants in n=18 of 384 (4.7%) unrelated individuals (n=13 MPMs; n=5 single primary melanomas) of European ancestry. Five variants were rare (minor allele frequency <0.001) or novel (two loss-of-function (LOF), one splice acceptor and two missense) and were predicted to be functionally significant, in five unrelated probands with MPMs (≥3 melanomas). We performed three-dimensional total body photography on both individuals with confirmed pathogenic LOF variants to characterise the dermatological phenotype. Total body naevus counts (≥2 mm diameter) were significantly higher (p=7.72×10-12) in carriers compared with a control population. Majority of naevi were on the probands' back and lower limb regions, where only mild to moderate ultraviolet (UV) damage was observed. Conversely, the head/neck region, where both probands exhibited severe UV damage, had comparably fewer naevi. We hypothesise that carriage of functionally significant POT1 variants is associated with increased naevus counts generally, and naevi >5 mm in diameter specifically and the location of these are independent of UV damage.

Australian researcher's perspectives on the Australian industry-led moratorium on genetic tests in life insurance.

Fear of insurance discrimination can inhibit genetic research participation. In 2019, an industry-led partial moratorium on using genetic results in Australian life insurance underwriting was introduced. This mixed-methods study used online surveys (n = 59 participants) and semi-structured interviews (n = 22 participants) to capture researchers' perceptions about the moratorium. 66% (n = 39/59) were aware of the moratorium before the survey. Of researchers returning genetic results, 56% (n = 22/39) reported that insurance implications were mentioned in consent forms, but a minority reported updating consent forms post-moratorium (n = 13/39, 33%). Most researchers reported that concerns regarding life insurers utilizing research results inhibited recruitment (35/59, 59%), and few perceived that the moratorium positively influenced participation (n = 9/39, 23%). These findings were supported by qualitative findings which revealed that genetic discrimination concerns were a major issue for some individuals, though these concerns could be eclipsed by the promise of a diagnosis through research participation. The majority thought a regulatory solution should be permanent (n = 34/51, 67%), have financial limits of at least ≥1,000,000 AUD (37/51, 73%), and involve government oversight/legislation (n = 44/51, 86%). In an era where an increasing number of research studies involve genomics as a primary or secondary objective, it is crucial that we have regulatory solutions to address participants' hesitation.

Human Genetics Society of Australasia Position Statement: Predictive and Presymptomatic Genetic Testing in Adults and Children.

This Position Statement provides guidelines for health professionals who work with individuals and families seeking predictive genetic testing and laboratory staff conducting the tests. It presents the major practical, psychosocial and ethical considerations associated with presymptomatic and predictive genetic testing in adults who have the capacity to make a decision, children and young people who lack capacity, and adults living with reduced or fluctuating cognitive capacity.Predictive Testing Recommendations: (1) Predictive testing in adults, young people and children should only be offered with pretest genetic counseling, and the option of post-test genetic counseling. (2) An individual considering whether to have a predictive test should be supported to make an autonomous and informed decision. Regarding Children and Young People: (1) Predictive testing should only be offered to children and young people for conditions where there is likely to be a direct medical benefit to them through surveillance, use of prevention strategies, or other medical interventions in the immediate future. (2) Where symptoms are likely to develop in childhood, in the absence of direct medical benefit from this knowledge, genetic health professionals and parents/guardians should discuss whether undertaking predictive testing is the best course of action for the child and the family as a whole. (3) Where symptoms are likely to develop in adulthood, the default position should be to postpone predictive testing until the young person achieves the capacity to make an autonomous and informed decision. This is applicable regardless of whether there is some action that can be taken in adulthood.

Narrative therapy and family therapy in genetic counseling: A scoping review.

Genetic counseling facilitates psychological and social adaptation in clients and families. Two psychotherapeutic approaches, narrative and family therapy foster client adaptation to adverse situations and may enhance the genetic counseling process. This scoping review aimed to describe the applications of narrative therapy and family therapy in genetic counseling, and to document the actual and perceived value of these approaches in a genetic counseling setting. Nine original research articles and six commentary articles met the study inclusion criteria. Original articles reported on positive client attitudes when these approaches were applied to hereditary cancer and Huntington disease settings. Five studies applied either approach in group sessions, where safety was key to positive outcomes, including sharing lived experiences and coping strategies. Balanced utilization of structured and open elements in group sessions maximized a sense of control, while also allowing for opportunity to self-disclose. Narrative therapy interventions were time efficient and were reported to foster connection with others and shape a new adaptive narrative centered around strengths. Family therapy approaches, based on experiential family therapy, the intersystem model, object relations family therapy, and the social ecology model, required a greater time commitment, but promoted disclosure of complex feelings and diffused tension. Family therapy genogram tools were feasible in practice, easy to implement, and effective at identifying communication barriers. Commentary articles highlighted the alignment of both approaches with genetic counseling goals and their potential value in practice. Utilization of psychotherapeutic approaches can improve counselors' ability to shape sessions, enhance insight and optimize efficacy, and flexibility in moving between models can maximize impact. This review highlights the paucity of studies investigating the efficacy of these psychotherapeutic approaches in the genetic counseling context and the need for more outcomes-based research on the utilization of narrative or family therapy in genetic counseling practice.

The ATM Ser49Cys Variant Effects ATM Function as a Regulator of Oncogene-Induced Senescence.

An apical component of the cell cycle checkpoint and DNA damage repair response is the ataxia-telangiectasia mutated (ATM) Ser/Thr protein kinase. A variant of ATM, Ser49Cys (rs1800054; minor allele frequency = 0.011), has been associated with an elevated risk of melanoma development; however, the functional consequence of this variant is not defined. ATM-dependent signalling in response to DNA damage has been assessed in a panel of patient-derived lymphoblastoid lines and primary human melanocytic cell strains heterozygous for the ATM Ser49Cys variant allele. The ATM Ser49Cys allele appears functional for acute p53-dependent signalling in response to DNA damage. Expression of the variant allele did reduce the efficacy of oncogene expression in inducing senescence. These findings demonstrate that the ATM 146C>G Ser49Cys allele has little discernible effect on the acute response to DNA damage but has reduced function observed in the chronic response to oncogene over-expression. Analysis of melanoma, naevus and skin colour genomics and GWAS analyses have demonstrated no association of this variant with any of these outcomes. The modest loss of function detected suggest that the variant may act as a modifier of other variants of ATM/p53-dependent signalling.

Germline ERBB3 mutation in familial non-small-cell lung carcinoma: expanding ErbB's role in oncogenesis.

Lung cancer is the commonest cause of cancer deaths worldwide. Although strongly associated with smoking, predisposition to lung cancer is also heritable, with multiple common risk variants identified. Rarely, dominantly inherited non-small-cell lung cancer (NSCLC) has been reported due to somatic mutations in EGFR/ErbB1 and ERBB2. Germline exome sequencing was performed in a multi-generation family with autosomal dominant NSCLC, including an affected child. Tumour samples were also sequenced. Full-length wild-type (wtErbB3) and mutant ERBB3 (mutErbB3) constructs were transfected into HeLa cells. Protein expression, stability, and subcellular localization were assessed, and cellular proliferation, pAkt/Akt and pERK levels determined. A novel germline variant in ERBB3 (c.1946 T > G: p.Iso649Arg), coding for receptor tyrosine-protein kinase erbB-3 (ErbB3), was identified, with appropriate segregation. There was no loss-of-heterozygosity in tumour samples. Both wtErbB3 and mutErbB3 were stably expressed. MutErbB3-transfected cells demonstrated an increased ratio of the 80 kDa form (which enhances proliferation) compared with the full-length (180 kDa) form. MutErbB3 and wtErbB3 had similar punctate cytoplasmic localization pre- and post-epidermal growth factor stimulation; however, epidermal growth factor receptor (EGFR) levels decreased faster post-stimulation in mutErbB3-transfected cells, suggesting more rapid processing of the mutErbB3/EGFR heterodimer. Cellular proliferation was increased in mutErbB3-transfected cells compared with wtErbB3 transfection. MutErbB3-transfected cells also showed decreased pAkt/tAkt ratios and increased pERK/tERK 30 min post-stimulation compared with wtErbB3 transfection, demonstrating altered signalling pathway activation. Cumulatively, these results support this mutation as tumorogenic. This is the first reported family with a germline ERBB3 mutation causing heritable NSCLC, furthering understanding of the ErbB family pathway in oncogenesis.

Models of communication for polygenic scores and associated psychosocial and behavioral effects on recipients: A systematic review.

PURPOSE: This study aimed to systematically review current models for communicating polygenic scores (PGS) and psycho-behavioral outcomes of receiving PGSs. METHODS: Original research on communicating PGSs and reporting on psycho-behavioral outcomes was included. Search terms were applied to 5 databases and were limited by date (2009-2021). RESULTS: In total, 28 articles, representing 17 studies in several disease settings were identified. There was limited consistency in PGS communication and evaluation/reporting of outcomes. Most studies (n = 14) presented risk in multiple ways (ie, numerically, verbally, and/or visually). Three studies provided personalized lifestyle advice and additional resources. Only 1 of 17 studies reported using behavior change theory to inform their PGS intervention. A total of 8 studies found no evidence of long-term negative psychosocial effects up to 12 months post result. Of 14 studies reporting on behavior, 9 found at least 1 favorable change after PGS receipt. When stratified by risk, 7 out of 9 studies found high PGS was associated with favorable changes including lifestyle, medication, and screening. Low-risk PGS was not associated with maladaptive behaviors (n = 4). CONCLUSION: PGS has the potential to benefit health behavior. High variability among studies emphasizes the need for developing standardized guidelines for communicating PGSs and evaluating psycho-behavioral outcomes. Our findings call for development of best communication practices and evidence-based interventions informed by behavior change theories.

Development and evaluation of a novel educational program for providers on the use of polygenic risk scores.

PURPOSE: This study aimed to develop an online educational program for using polygenic risk score (PRS) for breast and ovarian cancer risk assessments and to evaluate the impact on the attitudes, confidence, knowledge, and preparedness of genetic health care providers (GHPs). METHODS: The educational program comprises an online module that covers the theoretical aspects of PRS and a facilitated virtual workshop with prerecorded role-plays and case discussions. Data were collected in pre- and posteducation surveys. Eligible participants were GHPs working in Australian familial cancer clinics registered to recruit patients for a breast and ovarian cancer PRS clinical trial (n = 12). RESULTS: A total of 124 GHPs completed the PRS education, of whom 80 (64%) and 67 (41%) completed the pre- and posteducation surveys, respectively. Before education, GHPs reported limited experience, confidence, and preparedness using PRS, but they recognized its potential benefits. After education, GHPs indicated improved attitudes (P ≤ .001), confidence (P ≤ .001), knowledge (P ≤ .001), and preparedness (P ≤ .001) to use PRS. Most GHPs thought that the program entirely met their learning needs (73%) and was completely relevant to their clinical practice (88%). GHPs identified PRS implementation barriers, including limited funding models, diversity issues, and need for clinical guidelines. CONCLUSION: Our education program improved GHP attitudes, confidence, knowledge, and preparedness for using PRS/personalized risk and provides a framework for the development of future programs.

The MC1R r allele does not increase melanoma risk in MITF E318K carriers.

BACKGROUND: Population-wide screening for melanoma is not cost-effective, but genetic characterization could facilitate risk stratification and targeted screening. Common Melanocortin-1 receptor (MC1R) red hair colour (RHC) variants and Microphthalmia-associated transcription factor (MITF) E318K separately confer moderate melanoma susceptibility, but their interactive effects are relatively unexplored. OBJECTIVES: To evaluate whether MC1R genotypes differentially affect melanoma risk in MITF E318K+ vs. E318K- individuals. MATERIALS AND METHODS: Melanoma status (affected or unaffected) and genotype data (MC1R and MITF E318K) were collated from research cohorts (five Australian and two European). In addition, RHC genotypes from E318K+ individuals with and without melanoma were extracted from databases (The Cancer Genome Atlas and Medical Genome Research Bank, respectively). χ2 and logistic regression were used to evaluate RHC allele and genotype frequencies within E318K+/- cohorts depending on melanoma status. Replication analysis was conducted on 200 000 general-population exomes (UK Biobank). RESULTS: The cohort comprised 1165 MITF E318K- and 322 E318K+ individuals. In E318K- cases MC1R R and r alleles increased melanoma risk relative to wild type (wt), P < 0.001 for both. Similarly, each MC1R RHC genotype (R/R, R/r, R/wt, r/r and r/wt) increased melanoma risk relative to wt/wt (P < 0.001 for all). In E318K+ cases, R alleles increased melanoma risk relative to the wt allele [odds ratio (OR) 2.04 (95% confidence interval 1.67-2.49); P = 0.01], while the r allele risk was comparable with the wt allele [OR 0.78 (0.54-1.14) vs. 1.00, respectively]. E318K+ cases with the r/r genotype had a lower but not significant melanoma risk relative to wt/wt [OR 0.52 (0.20-1.38)]. Within the E318K+ cohort, R genotypes (R/R, R/r and R/wt) conferred a significantly higher risk compared with non-R genotypes (r/r, r/wt and wt/wt) (P < 0.001). UK Biobank data supported our findings that r did not increase melanoma risk in E318K+ individuals. CONCLUSIONS: RHC alleles/genotypes modify melanoma risk differently in MITF E318K- and E318K+ individuals. Specifically, although all RHC alleles increase risk relative to wt in E318K- individuals, only MC1R R increases melanoma risk in E318K+ individuals. Importantly, in the E318K+ cohort the MC1R r allele risk is comparable with wt. These findings could inform counselling and management for MITF E318K+ individuals.

A step forward, but still inadequate: Australian health professionals' views on the genetics and life insurance moratorium.

BACKGROUND: In 2019, the Australian life insurance industry introduced a partial moratorium (ban) limiting the use of genetic test results in life insurance underwriting. The moratorium is industry self-regulated and applies only to policies below certain financial limits (eg, $500 000 of death cover). METHODS: We surveyed Australian health professionals (HPs) who discuss genetic testing with patients, to assess knowledge of the moratorium; reported patient experiences since its commencement; and HP views regarding regulation of genetic discrimination (GD) in Australia. RESULTS: Between April and June 2020, 166 eligible HPs responded to the online survey. Of these, 86% were aware of the moratorium, but <50% had attended related training/information sessions. Only 16% answered all knowledge questions correctly, yet 69% believed they had sufficient knowledge to advise patients. Genetics HPs' awareness and knowledge were better than non-genetics HPs' (p<0.05). There was some reported decrease in patients delaying/declining testing after the moratorium's introduction, however, 42% of HPs disagreed that patients were more willing to have testing post-moratorium. Although many (76%) felt the moratorium resolved some GD concerns, most (88%) still have concerns, primarily around self-regulation, financial limits and the moratorium's temporary nature. Almost half (49%) of HPs reported being dissatisfied with the moratorium as a solution to GD. The majority (95%) felt government oversight is required, and 93% felt specific Australian legislation regarding GD is required. CONCLUSION: While the current Australian moratorium is considered a step forward, most HPs believe it falls short of an adequate long-term regulatory solution to GD in life insurance.

Human Genetics Society of Australasia Position Statement: Genetic Testing and Personal Insurance Products in Australia.

The expansion of genetic and genomic testing in clinical practice and research, and the growing market for direct-to-consumer genomic testing has led to increased awareness about the impact of this form of testing on insurance. Genetic or genomic information can be requested by providers of mutually rated insurance products, who may then use it when setting premiums or determining eligibility for cover under a particular product. Australian insurers are subject to relevant legislation and an industry led standard that was updated in 2019 to introduce a moratorium on the use of genetic test results in life insurance underwriting for policies

Human Genetics Society of Australasia Position Statement: Genetic Carrier Testing for Recessive Conditions.

This Position Statement provides guidelines to assist all health professionals who receive requests for carrier testing and laboratory staff conducting the tests.In this Statement, the term 'carrier testing' refers to genetic testing in an individual to determine whether they have inherited a pathogenic variant associated with an autosomal or X-linked recessive condition previously identified in a blood relative. Carrier testing recommendations: (1) Carrier testing should only be performed with the individual's knowledge and consent; (2) An individual considering (for themselves, or on behalf of another) whether to have a carrier test should be supported to make an informed decision; (3) The mode of inheritance, the individual's personal experience with the condition, and the healthcare setting in which the test is being performed should be considered when determining whether carrier testing should be offered by a genetic health professional. Regarding children and young people: Unless there is direct medical benefit in the immediate future, the default position should be to postpone carrier testing until the child or young person can be supported to make an informed decision. There may be some specific situations where it is appropriate to facilitate carrier testing in children and young people (see section in this article). In such cases, testing should only be offered with pre- and post-test genetic counseling in which genetic health professionals and parents/guardians should explore the rationale for testing and the interests of the child and the family.

Australasian genetic counselors' attitudes toward disability and prenatal testing: Findings from a cross-sectional survey.

Diagnostic genetic testing and non-invasive prenatal testing (NIPT) for conditions associated with disability are becoming increasingly available to consumers. This genetic information can be used in the disability setting to inform factors such as prognosis, management, and reproductive decision-making. Genetic counselors (GCs) play an important role in the provision of genetic testing and NIPT, and their attitudes toward disability can influence how genetic information is communicated and shape patients' responses. This study aimed to evaluate and describe Australasian GCs' experience with and attitudes toward disabilities to identify potential biases and training needs. A cross-sectional survey was distributed to 400 GCs registered with the Human Genetics Society of Australasia. Of the 106 respondents (participation rate: 26%), a significantly greater proportion were more comfortable interacting with individuals with physical disability as compared to intellectual disability (p < 0.001). GCs with personal experiences with disabilities reported significantly greater comfort interacting with people with intellectual disability than those without experience (p = 0.012). Qualitative analysis revealed discomfort was less reflective of bias than inexperience and apprehension about communicating disrespectfully. GCs believed people with disabilities experience discrimination and that having a disability could make a person stronger, wiser, and more motivated. Most GCs viewed prenatal testing for disabilities positively as it allowed for decisions regarding continuing the pregnancy and/or provided opportunity to prepare. Challenges identified for prenatal counseling included negative societal attitudes and the low visibility of disability. GCs felt that 'personal beliefs' was the primary factor influencing the decision to terminate a pregnancy affected by disability. These findings highlight important education and training needs for GCs to improve preparedness and comfort when communicating with people with a disability.

The emerging field of polygenic risk scores and perspective for use in clinical care.

Genetic testing is used widely for diagnostic, carrier and predictive testing in monogenic diseases. Until recently, there were no genetic testing options available for multifactorial complex diseases like heart disease, diabetes and cancer. Genome-wide association studies (GWAS) have been invaluable in identifying single-nucleotide polymorphisms (SNPs) associated with increased or decreased risk for hundreds of complex disorders. For a given disease, SNPs can be combined to generate a cumulative estimation of risk known as a polygenic risk score (PRS). After years of research, PRSs are increasingly used in clinical settings. In this article, we will review the literature on how both genome-wide and restricted PRSs are developed and the relative merit of each. The validation and evaluation of PRSs will also be discussed, including the recognition that PRS validity is intrinsically linked to the methodological and analytical approach of the foundation GWAS together with the ethnic characteristics of that cohort. Specifically, population differences may affect imputation accuracy, risk magnitude and direction. Even as PRSs are being introduced into clinical practice, there is a push to combine them with clinical and demographic risk factors to develop a holistic disease risk. The existing evidence regarding the clinical utility of PRSs is considered across four different domains: informing population screening programs, guiding therapeutic interventions, refining risk for families at high risk, and facilitating diagnosis and predicting prognostic outcomes. The evidence for clinical utility in relation to five well-studied disorders is summarized. The potential ethical, legal and social implications are also highlighted.

Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice.

The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. LoF WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia.

Anatomic Distribution of Cherry Angiomas in the General Population.

BACKGROUND: Cherry angiomas are common benign vascular skin lesions of unknown aetiology, found largely on the trunk. However, their exact anatomic distribution besides their truncal predisposition, and how they manifest in the general population, has not been characterised. METHODS: Three-dimensional (3D) total body imaging was obtained from 163 adult participants of a general population cohort study in Brisbane, Australia. Demographic, phenotypic, and sun behaviour characteristics were collected using a standard questionnaire along with history of melanoma and keratinocyte cancers. Cherry angiomas were identified using an automated classification algorithm with a sensitivity of 87% and a specificity of 99%, developed specifically for this study population. RESULTS: The 3D total body images of 163 participants were analysed. Participants had a median age of 57 years and 61% were male. On average, males had more angiomas than females (median of 16 vs. 12) and the number and size of cherry angiomas increased with age. In addition to male sex and age, an increase in angiomas was associated with Caucasian ancestry other than British/Irish only, fair skin colour opposed to medium/olive, having green/hazel eyes compared to blue/grey, and personal history of melanoma. The most common site for cherry angiomas was the front trunk, followed by the back. Interestingly, although males had more angiomas overall, females had more angiomas on the legs. CONCLUSION: Describing the distribution of cherry angiomas by body site is an important step towards further understanding of the aetiology of angiomas. While personal history of melanoma is associated with an increased number of cherry angiomas, whether this association is prognostic, co-occurs with development of melanoma, or is merely fortuitous requires further investigation.

The impact of Marfan syndrome on an Aboriginal Australian family: 'I don't like it as much as I don't like cancer'.

Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder. Aortic dilatation/dissection and ectopia lentis are the most severe features, which affect physical functioning and psychological well-being. In Aboriginal Australians, there is little psychosocial research on genetic conditions. This study explored the physical, psychological, and practical impacts of MFS on Aboriginal Australians. Eighteen (8 affected and 10 unaffected) members of a large Aboriginal Australian family with MFS participated in an ethically approved study. Semi-structured qualitative interviews were conducted, transcribed verbatim, and analyzed thematically. All individuals reported challenges from MFS, negatively affecting day-to-day living. Severe vision impairment was perceived as the greatest challenge, contributing to feelings of stigma and exclusion. With aging, concerns shifted toward cardiac complications. The unpredictability of lens dislocation and aortic dissection was reported to be psychologically challenging. Participants described MFS-related barriers to obtaining and retaining employment, especially following cardiac surgery; with consequential psychological and financial hardships. Participants articulated that their cultural drive to support the ill and respectfully mourn the deceased, regardless of distance, resulted in a significant financial burden. Additionally, when hospitalization and/or funerals occurred, financially solvent individuals were expected to share resources, without any expectation of repayment or reciprocity (i.e., 'demand sharing', common in Aboriginal Australian culture). This study documents the nature and pervasiveness of uncertainty for both affected and unaffected members of an MFS family. Many reported challenges are consistent with other MFS cohorts (including stigma, social exclusion, and unemployment). However, our findings suggest that cultural values may exacerbate the financial costs of MFS for Aboriginal Australians.

A family with partially penetrant multicentric carpotarsal osteolysis due to gonadal mosaicism: First reported case.

Multicentric carpotarsal osteolysis (MCTO) is an autosomal dominant condition characterized by carpal-tarsal abnormalities; over half of affected individuals also develop renal disease. MCTO is caused by mutations of MAFB; however, there is no clear phenotype-genotype correlation. We describe the first reported family of variable MCTO phenotype due to mosaicism: the proband had classical skeletal features and renal involvement due to focal segmental glomerulosclerosis (FSGS), and the father had profound renal impairment due to FSGS, necessitating kidney transplantation. Mosaicism was first suspected in this family due to unequal allele ratios in the sequencing chromatograph of the initial blood sample of proband's father and confirmed by sequencing DNA extracted from the father's hair, collected from different bodily parts. This case highlights the need for a high index of clinical suspicion to detect low-level parental mosaicism, as well as a potential role for MAFB mutation screening in individuals with isolated FSGS.

Waiting for a diagnosis in Rubinstein-Taybi: The journey from "ignorance is bliss" to the value of "a label".

The journey to receiving a diagnosis for rare genetic disease can be long and emotionally impactful. This study describes parental experiences of receiving their child's diagnosis of Rubinstein-Taybi syndrome (RTS), a rare genetic condition characterized by growth and developmental delay together with dysmorphic features. Parents from the RTS Australia support group participated in qualitative, semi-structured phone interviews, which were transcribed verbatim and thematically analyzed. Questions focused on psychosocial challenges and benefits pre and post-diagnosis. Ten mothers and three fathers participated, with the mean age of diagnosis being 8 months. Parents reported positive psychological effects from a slight delay in diagnosis, and negative effects from an extended diagnostic delay, suggesting the ideal time for a parent to receive a diagnosis lies in the post attachment stage, prior to the development of significant parental concerns. This stage would vary depending on condition severity. Parents desired a diagnosis to reduce uncertainty; however, uncertainty remained post diagnosis, and shifted its focus from broadly encompassing etiology and prognosis, to specifically focusing on concerns regarding severity within the spectrum. Perceived benefits of a diagnosis mainly centered on the provision of a label. Parents articulated that a label increased social acceptance, enhanced coping, promoted communication, and improved access to medical, financial, and support services. This study provides insights into the experience of families prior to and following receipt of a diagnosis. It also highlights the possibility of an optimal time window to receive a diagnosis; in which bonding is maximized and parental distress is minimized.