Genetic Counseling Issues Research Articles

Isolated dentinogenesis imperfecta: Novel DSPP variants and insights on genetic counselling

ObjectiveDentinogenesis imperfecta (DI) is an inherited dentin defect and may be isolated or associated with disorders such as osteogenesis imperfecta, odontochondrodysplasia Ehler-Danlos and others. Isolated DI is caused mainly by pathogenic variants in DSPP gene and around 50 different variants have been described in this gene. Herein, we report on 19 patients from two unrelated Egyptian families with isolated DI. Additionally, we focused on genetic counselling of the two families.Materials and methodsThe patients were examined clinically and dentally. Panoramic X-rays were done to some patients. Whole exome sequencing (WES) and Sanger sequencing were used.ResultsWES revealed two new nonsense variants in DSPP gene, c.288T > A (p.Tyr96Ter) and c.255G > A (p.Trp85Ter). Segregation analysis by Sanger sequencing confirmed the presence of the first variant in all affected members of Family 1 while the second variant was confirmed to be de novo in the patient of Family 2.Conclusions and clinical relevanceOur study extends the number of DSPP pathogenic variants and strengthens the fact that DSPP is the most common DI causative gene irrespective of patients’ ethnicity. In addition, we provide insights on genetic counseling issues in patients with inherited DSPP variants taking into consideration the variable religion, culture and laws in our society.

Exploring the impact of the reclassification of a hereditary cancer syndrome gene variant: emerging themes from a qualitative study

The complexity of genetic variant interpretation means that a proportion of individuals who undergo genetic testing for a hereditary cancer syndrome will have their test result reclassified over time. Such a reclassification may involve a clinically significant upgrade or downgrade in pathogenicity, which may have significant implications for medical management. To date, few studies have examined the psychosocial impact of a reclassification in a hereditary cancer syndrome context. To address this gap, semi-structured telephone interviews were performed with eighteen individuals who had a BRCA1, BRCA2 or Lynch syndrome-related (MLH1, MSH2, MSH6 or PMS2) gene variant reclassified. The interviews were analysed utilising an inductive, qualitative approach and emergent themes were identified by thematic analysis. Variable levels of recall amongst participants were found. Common motivations for initial testing included a significant personal and/or family history of cancer and a desire to “find an answer”. No individual whose uncertain result was upgraded reported negative psychosocial outcomes; most reported adapting to their reclassified result and appraised their genetic testing experience positively. However, individuals whose likely pathogenic/pathogenic results were downgraded reported feelings of anger, shock and sadness post reclassification, highlighting that additional psychosocial support may be required for some. Genetic counselling issues and recommendations for clinical practice are outlined.

Identification of Biallelic dystrophin gene variants during maternal carrier testing for Becker muscular dystrophy and review of the DMD exon 49-51 deletion phenotype.

Dystrophinopathies are X-linked recessive conditions caused by pathogenic variants in the dystrophin (DMD) gene. In a family that included two boys with Becker muscular dystrophy (BMD) due to a DMD deletion of exons 45-47, maternal carrier testing unexpectedly identified biallelic DMD deletions of exons 45-47 and 49-51. The patient's mild phenotype in the setting of biallelic DMD variants prompted further investigation of the exon 49-51 deletion in particular, via literature review and retrospective chart review of patients who have been evaluated in our institution's comprehensive neuromuscular center and/or diagnosed in our clinical genetic testing laboratory. To our knowledge, this is only the fifth case of confirmed biallelic DMD variants in a female. In males, the DMD exon 49-51 deletion appears to result in a mild BMD phenotype with low or normal creatine kinase levels. This deletion comprised 19% (4/21) of dystrophinopathies diagnosed by chromosomal microarray (CMA) in males during the past ten years in our clinical laboratory. Most individuals identified by chart review were diagnosed through CMA, despite the fact that microarray was genome-wide and not DMD-specific. This case raised important genetic counseling issues. The DMD exon 49-51 deletion appears to cause a variable but generally mild BMD phenotype. Its relatively frequent detection by CMA suggests it may be underdiagnosed.

Oculocutaneous albinism in southern Africa: Historical background, genetic, clinical and psychosocial issues.

Albinism is an inherited condition associated with significant depigmentation of the skin, hair and eyes. It occurs in every population with varying frequency, and narratives of people with albinism have been recorded since 200 BC. In southern Africa albinism is common, about 1 in 4000 people are affected, but it remains a poorly understood condition surrounded by myths and superstition. This article provides a historical background on oculocutaneous albinism (OCA) in southern Africa and presents relevant information from the literature regarding epidemiology, genetics and genetic counselling, health, psychosocial and cultural issues, and medical care. There are several recessively inherited types of OCA and a mutation, responsible for about 80% of South African variants, has been identified in OCA type 2. The physical characteristics associated with albinism, that is, sun-sensitive skin and low vision, can be managed. However, people with OCA in Africa also experience psychosocial issues, such as discrimination, because of the various superstitious beliefs and attitudes held in the community. Management should include medical care for health problems, appropriate adjustment of the schooling context and genetic counseling. In addition, widespread public awareness programmes are required to increase the knowledge of the genetic causes of OCA and of the nature of genetic counselling, to address the negative attitudes in the community, to reduce the marginalisation and stigmatization of people with albinism and to improve their quality of life.

Complexities in Genetic Counseling and Testing of Huntington's Disease: A Perspective from India.

Huntington's Disease (HD) is an autosomal dominant, progressive neuropsychiatric illness caused by CAG repeat expansion. The high penetrance of the mutation and limited treatment options make it challenging for patients and caretakers. Proper counseling enables families to cope better and make informed life choices. To explore some complex issues in genetic counseling and testing (GCAT) in HD. Vignettes of patients who underwent genetic testing along with pre and post-test counseling at our GCAT clinic. Case 1: Diagnosis of juvenile HD meant that the healthy parent was an obligate carrier of the mutation. Case 2: Consanguinity resulted in a dense prevalence of HD and >50% risk for the progeny. Case 3: Predictive testing in youth with healthy parents but affected uncles and aunts revealed a HD expansion. HD can present with complex inheritance patterns and proper counseling is necessary for better outcomes.

A Young Bangladeshi Boy with Primary Ciliary Dyskinesia (Kartagener’s Syndrome): A Rare Case

Kartagener’s syndrome, an autosomal recessive inherited disorder, is a subgroup of primary ciliary dyskinesias (PCD). This genetic disorder manifests from early life which distinguishes it from acquired mucociliary disorders. Kartagener’s syndrome presents as a classical triad of situs inversus, sinusitis and bronchiectasis occurring majorly due to impaired ciliary motility. A 16 year-old boy from Fulbaria, Mymensingh with left sided consolidation for 1 month and recurrent episodes of nasal congestion and lower respiratory tract infection (LRTI) since his childhood. Clinical and imaging findings revealed left sided consolidation, chronic sinusitis, bronchiectasis, dextrocardia, and situs inversus. He was treated with orally administered antibiotics, bronchodilators, mucolytics, and chest physiotherapy. He was symptomatically better with the above therapy, and started on a long-term low-dose prophylactic antibiotic. As there is no easy, reliable non-invasive diagnostic test for Kartagener’s syndrome and the correct diagnosis is often delayed by years, it may cause chronic respiratory problems with reduced quality of life. Genetic counseling and fertility issues should be addressed once Kartagener’s syndrome is diagnosed.
 CBMJ 2022 January: vol. 11 no. 01 P: 56-60

Are We Ready for Newborn Genetic Screening? A Cross-Sectional Survey of Healthcare Professionals in Southeast China.

ObjectivesTo understand the knowledge, attitude, willingness, and ability of healthcare professionals working in newborn screening (NBS) centers regarding newborn genetic screening (nGS).MethodsThe questionnaire consisted of four sections with 27 questions and the data were collected by the WJX platform. All participants accessed the questionnaire by scanning a specific QR code with their mobile phones. Two researchers independently completed the summary and analysis.ResultsA total of 258 valid questionnaires were collected from 43 NBS centers in six provinces of southeast China. In total, 209 (81.01%) participants were interested in nGS, and almost all participants (97.67%) thought that nGS was necessary in China. About 89.53% of participants thought that it could be used to effectively expand the diseases that could be screened, but 72.87% also worried about the inability to provide genetic counseling. About 55.34% suggested that nGS and tandem mass spectrometry (TMS) screening could be applied in a unite screening mode. The higher the institution and personal education levels, the higher the interest healthcare professionals displayed toward nGS. However, they also showed greater concern about the inability to provide genetic counseling and ethical issues. If a center had engaged in TMS screening, its staff would have been more likely to believe that nGS had great advantages. In addition, most participants had ethical concerns, such as “the psychological burden caused by carrying information regarding adult morbidity risk.”ConclusionMost participants were interested and considered nGS necessary. The inability to provide genetic counseling may be the primary impediment to clinical practice. Three important influencing factors were level of education, institution level, and engagement in TMS screening.

Genetic counseling research and COVID-19: A lesson in resiliency.

GenCOUNSEL is the largest genetic counseling research grant awarded to date and brings together experts in genetic counseling, genomics, law and policy, health services implementation, and health economics research. It is the first project of its kind to examine the genetic counseling issues associated with the clinical implementation of genome‐wide sequencing (exome and genome sequencing). GenCOUNSEL is a Canadian‐based, multi‐method research study that takes place over a variety of sites, including non‐clinical, clinical, and laboratory research sites and includes the training of undergraduate and graduate students. The COVID‐19 pandemic will likely have a lasting impact on genetic counseling service delivery, research, and training. Almost every aspect of the GenCOUNSEL research project has been impacted by the COVID‐19 pandemic. Here we describe how our research recruitment strategies, methods, resource allocation, and training capacity have been affected. We discuss ways that we have adapted to the pandemic including revision of our research methods and work to understand the barriers in order to optimize opportunities. We finish with take‐home messages to fellow researchers highlighting the importance of resiliency in genetic counseling research.

Genetic testing in dementia-A medical genetics perspective.

When a genetic cause is suspected in a person with dementia, it creates unique diagnostic and management challenges to the treating clinician. Many clinicians may be unaware of the practicalities surrounding genetic testing for their patients, such as when to test and what tests to use and how to counsel patients and their families. This review was conducted to provide guidance to clinicians caring for patients with dementia regarding clinically relevant genetics. We searched PubMed for studies that involved genetics of dementia up to March 2020. Patient file reviews were also conducted to create composite cases. In addition to families where a strong Mendelian pattern of family history is seen, people with younger age of onset, especially before the age of 65 years were found to be at an increased risk of harbouring a genetic cause for their dementia. This review discusses some of the most common genetic syndromes, including Alzheimer disease, frontotemporal dementia, vascular dementia, Parkinson disease dementia/dementia with Lewy bodies and some rarer types of genetic dementias, along with illustrative clinical case studies. This is followed by a brief review of the current genetic technologies and a discussion on the unique genetic counselling issues in dementia. Inclusion of genetic testing in the diagnostic pathway in some patients with dementia could potentially reduce the time taken to diagnose the cause of their dementia. Although a definite advantage as an addition to the diagnostic repository, genetic testing has many pros and cons which need to be carefully considered first.

Double heterozygosity for TP53 and BRCA1 mutations: clinical implications in populations with founder mutations.

The co-occurrence or double heterozygosity of pathogenic/likely pathogenic sequence variants (P/LPSVs) in major cancer susceptibility genes has rarely been reported. Such co-occurrence raises the issues of accurate genetic counseling, preferred recommended surveillance scheme, and the use of preimplantation genetic diagnosis (PGD). A clinical report of an Ashkenazi Jewish (AJ) family with co occurrence of two PSVs in BRCA1 and TP53 and a literature search. In an AJ family with a substantial history of cancer limited to the maternal side, two siblings co-harbored TP53 (c.733C>A; p.G245S) and the predominant 5266dup BRCA1 mutation, originating from the mother and the father, respectively. PGD is ongoing. Four families were thus far reported as double heterozygotes for both BRCA1/BRCA2 and TP53. Based on the limited available data, it seems that the phenotype in double PSV heterozygotes is not more severe than in single PSV carrier in either gene. This family highlights the need to genotype both parents, especially in populations with founder mutations, when a BRCA1 mutation is detected in an offspring, regardless of family history. The combination of mutations in these two genes presents a challenge for PGD since both genes are located on chromosome 17.

Rapid acute care genomics: Challenges and opportunities for genetic counselors.

Genomic medicine in pediatric acute care is showing great promise, with rapid results from exome and genome sequencing returned within days providing critically important information for treatment and management of seriously ill children. Many have suggested that rapid acute care genomics presents novel genetic counseling issues. This is due to the need for rapid response to referrals, the immense emotional distress that parents are likely to experience when their child is in acute care, and the unfamiliar environment of the acute care setting. To explore the practice of genetic counselors in this setting, we conducted qualitative interviews with 16 genetic counselors (GCs), representing a large proportion of GCs at the frontline of providing genetic counseling in acute care settings in Australia. Interviews revealed themes describing genetic counseling in acute care, including practical challenges of counseling within a rapid turnaround time, similarities with other contexts such as prenatal counseling, and the need for education of other health professionals. Interestingly, GCs did not raise concerns in the interviews for parents' ability to provide informed consent for rapid genomic sequencing. GCs also encountered practical and organizational challenges with counseling in this setting where 24-hr care is provided, at odds with traditional '9 to 5' Genetics service delivery. Working closely in a multidisciplinary team was common and participants believed that GCs are well positioned to take a leading role in the education of other health professionals as rapid acute care genomics becomes routine clinical practice. Despite views that genetic counseling practice in rapid acute care genomics is unique, these exploratory data suggest that GCs are flexible, adaptable, and sufficiently skilled to deliver patient-centered counseling in this setting. Our work indicates GCs are ready and willing to contribute at an early stage of adoption of genomic investigations in acute care.

Genetic Testing and Counseling in Metabolic Liver Disease: An Interactive Lecture for Medical Students.

IntroductionMedical students have limited opportunities to learn about current genetic testing. This session provided exposure to different types of testing and the complex issues that physicians may encounter when counseling patients on proper testing and interpreting results.MethodsWe designed a 1-hour interactive lecture for second-year medical students. We presented an overview of the topic, then applied the concepts to specific disorders and cases. Students were asked to answer questions regarding cases using an audience response system, and we used their responses as the basis for our in-class discussion. This session has been held twice, with 25 students attending in 2018 and 31 students in 2019. The session was also recorded so that additional students not in attendance could watch, and was available to 151 students in 2018 and 333 students in 2019.ResultsStudents answered questions via audience response system. There was a range of 47%–100% of students giving the correct answers in 2018, and 55%–93% in 2019. Exam questions covering genetic counseling issues were answered correctly by 66% and 77% of students in 2018, and 70% and 68% of students in 2019.DiscussionThis session provided an opportunity for medical students to be exposed to some of the complex ethical and psychosocial issues that may arise with genetic testing for liver disease and to consider how to navigate them. Using an audience response system during the lecture made the session more interactive and allowed the teacher to correct errors and teach based on the responses.

Huntington’s disease

Huntingtons disease is one of the most common hereditary neurodegenerative diseases, which remains practically incurable, inevitably leading to the disability of patients and premature death. A fairly wide prevalence in the world, the special severity of the course, the almost complete penetrance of the mutant gene, the peculiarity of clinical and genetic correlations in Huntingtons disease have attracted researchers specializing in neuroscience for many years. The study of the molecular neurobiology of Huntingtons disease over the past decades has largely contributed to significant progress in molecular biology, genetics, and many other biomedical disciplines. At the same time, Huntingtons disease has become a model disease in resolving issues of genetic counseling and prognostic testing in modern medical genetics. The review provides brief facts on the history of the study of the disease, including mapping and identification of the mutant gene. The issues of etiology and pathogenesis, molecular genetics of the disease, epidemiology, diagnostics, and differential diagnostics are discussed in detail. The spectrum of clinical manifestations of Huntingtons disease, its various forms, and course features are presented. From a modern perspective, the problem of developing valid biomarkers of both the manifest and the asymptomatic stages of the disease, as well as the course of the pathological process, are highlighted. The main issues of primary and secondary prevention of Huntingtons disease, bioethical principles of conducting genetic counseling for families burdened by this disease are outlined. The approaches to the symptomatic treatment of Huntingtons disease are described, a review of the main promising experimental therapeutic methods that can potentially slow down or stop the progression of the disease, as well as prevent its manifestation in asymptomatic carriers of the mutant gene, are presented. An important contribution of patient organizations to addressing issues affecting the interests of burdened families, scientific and clinical research on the disease was noted. Literature was searched and analyzed using the databases of Scopus, Web of Science, Pubmed (MedLine), eLibrary.

The Changing Landscape of Genetics in the Philippines

In the beginning, medical genetics was concerned only with rare single gene or chromosomal disorders. However, the Human Genome Project has made available information of invaluable diagnostic and therapeutic importance. It links the genome with human health.
 It is becoming clear that all diseases or medical conditions have a genetic component with a huge proportion of the general population having a recognized genetic disorder. Presently, there is greater appreciation of genetic contributions to normal physiologic processes, early disease detection, pathogenesis, prevention and susceptibility to disease, disease prognostication and monitoring, the development of innovative diagnostic tests and novel therapeutic approaches. Genetics is currently the driving force in medical research.
 While the papers in this special 2017 Genetics issue of Acta Medica Philippina give different perspectives on genetics, certain key themes have become evident in the submissions. We highlight birth defects, molecular genetics, cancer genetics, dysmorphology–craniofacial syndromes, the importance of folic acid, metabolic disorders, and genetic counselling issues. With the expansion of our genetic understanding of normal physiologic processes and disease, the role of the genetic counselor has also undoubtedly increased. The challenge is to make these genetic advances benefit people/ patients and the public. There is a need to educate them and make them aware of the different facets of genetics and its implications to the patient, their families and disseminate these information to the community.
 The integration of genetics into medical practice will occur at a different pace for all areas in medicine. Genetic technology is available and accessible for everyone with interest to do genetic research in their corresponding medical field.
 It is realized though that the Philippines, being a developing country, needs to recognize the burden imposed by genetic disorders and birth defects. There must be political will and commitment to sup port the implementation of these genetic services. Knowledge about genetic disorders and birth defects must be enhanced and the goals of genetic services in terms of both individual/family welfare and public health must be delineated with ethical principles and cultural diversity respected.
 Catherine Lynn T. Silao, MD, PhD, FPPS Guest EditorInstitute of Human GeneticsNational Institutes of HealthUniversity of the Philippines Manila

Ethical Issues in Genetic Counseling for Thalassemia

The complexity of genetic counseling in thalassemia is related to the ‘predictive nature’ of genetic information, impact and implications on other family members and ethical, legal and psychosocial...

Legal Challenges in Genetics, Including Duty to Warn and Genetic Discrimination.

This review will explore two legal issues in genetic counseling: genetic discrimination and the duty to warn. It emphasizes the complexity and variability of federal and state genetic nondiscrimination protections in the United States and how the many gaps in such protections may affect people pursuing genetic testing. The limited law addressing legal obligations genetic counselors owe at-risk relatives likely does not require counselors to warn relatives directly about genetic risks. Whether it permits them to make such disclosures, however, is more uncertain and may depend on the jurisdiction.

Prenatally diagnosed de novo segmental amplification or deletion by microarray-based comparative genomic hybridization: A retrospective study

ObjectivePrenatal diagnosis of de novo segmental amplification or deletion by microarray-based comparative genomic hybridization (array CGH) is uncommon. The study aimed to know about the incidence, abnormal ultrasound findings, and pregnancy outcomes of prenatally diagnosed de novo segmental amplification or deletion by array CGH. Materials and methodsBetween January 2014 and December 2017, we analyzed pregnant women who received prenatal array CGH (SurePrint G3 Human CGH Microarray Kit, 8 × 60K) at Chang Gung Memorial Hospital, Taiwan. Clinical data on maternal age, reason for fetal karyotyping, sonographic findings, gestational age at delivery, newborn birth weight, and associated anomalies, if any, were obtained by chart review. ResultsA total of 836 specimens (814 amniotic fluid samples, 4 cord blood samples, 18 chorionic villi samples) were analyzed by array CGH during the study period. Of the 56 cases with abnormal array CGH results, 40 had segmental amplification or deletion, 12 had trisomy, three had monosomy, and one had sex chromosome aneuploidy. Of these 40 cases with segmental amplification or deletion, 30 were inherited and 10 were de novo occurrences. The incidence of de novo segmental amplification or deletion was 1.2% (10/836). Abnormal prenatal ultrasound findings occurred in 40% (4/10) of de novo segmental amplification or deletion cases. Among these 10 pregnancies, nine were voluntarily terminated between 22 and 26 weeks of gestation and one was delivered at term. ConclusionsPrenatal diagnosis of de novo segmental amplification or deletion by array CGH raises important genetic counseling issues. In our series, the incidence of de novo segmental amplification or deletion in prenatal samples was 1.2%. Abnormal prenatal sonographic findings occurred in 40% of these de novo segmental amplification or deletion cases. Of these de novo segmental amplification or deletion pregnancies, 90% were voluntarily terminated.

Secondary actionable findings identified by exome sequencing: expected impact on the organisation of care from the study of 700 consecutive tests.

With exome/genome sequencing (ES/GS) integrated into the practice of medicine, there is some potential for reporting incidental/secondary findings (IFs/SFs). The issue of IFs/SFs has been studied extensively over the last 4 years. In order to evaluate their implications in care organisation, we retrospectively evaluated, in a cohort of 700 consecutive probands, the frequency and burden of introducing the search for variants in a maximum list of 244 medically actionable genes (genes that predispose carriers to a preventable or treatable disease in childhood/adulthood and genes for genetic counselling issues). We also focused on the 59 PharmGKB class IA/IB pharmacogenetic variants. We also compared the results in different gene lists. We identified variants (likely) affecting protein function in genes for care in 26 cases (3.7%) and heterozygous variants in genes for genetic counselling in 29 cases (3.8%). Mean time for the 700 patients was about 6.3 min/patient for medically actionable genes and 1.3 min/patient for genes for genetic counselling, and a mean time of 37 min/patients for the reinterpreted variants. These results would lead to all 700 pre-test counselling sessions being longer, to 55 post-test genetic consultations and to 27 secondary specialised medical evaluations. ES also detected 42/59 pharmacogenetic variants or combinations of variants in the majority of cases. An extremely low metabolizer status in genes relevant for neurodevelopmental disorders (CYP2C9 and CYP2C19) was found in 57/700 cases. This study provides information regarding the need to anticipate the implementation of genomic medicine, notably the work overload at various steps of the process.

Beyond the Brochure: Innovations in Clinical Counseling Practices for Prenatal Genetic Testing Options.

Remarkable advancements related to preconception and prenatal genetic screening have emerged in recent years. While technology and testing options are more numerous and complex; fundamental genetic counseling issues remain the same. It is essential that with any prenatal genetic testing, women have an opportunity to make informed and autonomous decisions that are consistent with their personal needs and values. Opportunities to discuss testing options, including potential benefits and limitations, are often limited in obstetric visits due to time constraints or lack of sufficient provider education. As genetic testing is not considered a routine component of antepartum care, review of information regarding testing options is imperative so women can decide which, if any, testing to pursue. Developing new strategies to address the growing complexity of prenatal testing while ensuring provider education is accurate is crucial in imparting evidence-based care. This article will arm providers with the knowledge needed to educate women about currently available prenatal genetic screening and diagnostic tests along with guidance on the essential elements and importance of genetic counseling.

SU46 - PSYCHIATRIC GENETIC COUNSELING: CHALLENGES IN AUTISM SPECTRUM DISORDERS

Autism Spectrum Disorders (ASD) have one of the highest estimates of heritability among psychiatric conditions. Genetic testing is now considered standard of care for diagnosis of ASD etiology, and is increasingly available, affordable, and offered to patients and their families. The 2013 American College of Medical Genetics Practice Guidelines estimates a genetic diagnostic yield of 30–40% in ASD cases, recommending Chromosome Microarray (CMA), single gene testing such as FMR1, as well as other testing such as metabolic studies. As of 2017, more than 20 academic and commercial laboratories have developed clinical genetic tests specific for ASD, which are being marketed as diagnostic testing to clinicians worldwide. However, these gene panels often have low clinical validity, and often include genes where the associations between the loci and ASD are unclear. Little is known regarding the practical experience of individuals with ASD undergoing genetic testing. Here, we present five illustrative cases and suggest standardized approaches for genetic counseling in ASD. Since 2013, clinical genetic testing has been routinely offered to individuals with ASD in our Genetics clinic. The most common test offered was CMA, followed by FMR1 and whole exome sequencing. Through retrospective chart review, five representative cases were selected to highlight the diagnostic and counseling complexities. From 2013 to 2016, we provided genetic counseling to 29 individuals with ASD, resulting in at least a partial genetic diagnosis in 34% of cases, a variant of unknown significance in 10% of cases, and incidental findings in 7% of cases. We present five cases of nonsyndromic ASD with variable genetic testing results (1q21.1 deletion, 16p11.2 duplication, 15q13.3 duplication, AUTS2, 47, XYY) and discuss the genetic counseling issues for each. In our collective experience with these and other cases, we have found that diagnostic challenges include phenotypic and locus heterogeneity, variable expressivity, reduced penetrance, causative versus risk alleles, and changing genetic associations as research progresses. Psychosocial challenges include misleading information online, illness representation beliefs of patients and families, stigma, guilt and shame, and family communication. It is not enough to know that certain genetic factors are associated with ASD. Translating this information in a meaningful way for patients and families is the ultimate goal of all clinically-directed research. The reactions of the families described in this case series illustrate these challenges. We recommend standardizing informed consent for genetic testing in ASD, especially regarding the inherent uncertainties, and to include referral to a clinical genetic specialist if available. Careful and informed genetic counseling is crucial and may lead to improved coping and adaptation, and may reduce negative consequences of stigma and discrimination.