Sharyn Lincoln

Clinical genetic testing for patients with autism spectrum disorders

BACKGROUND: Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established. PATIENTS AND METHODS: A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008. Clinical genetic testing included G-banded karyotype, fragile X testing, and chromosomal microarray (CMA) to test for submicroscopic genomic deletions and duplications. Diagnostic yield of clinically significant genetic changes was compared. RESULTS: Karyotype yielded abnormal results in 19 of 852 patients (2.23% [95% confidence interval (CI): 1.73%–2.73%]), fragile X testing was abnormal in 4 of 861 (0.46% [95% CI: 0.36%–0.56%]), and CMA identified deletions or duplications in 154 of 848 patients (18.2% [95% CI: 14.76%–21.64%]). CMA results for 59 of 848 patients (7.0% [95% CI: 5.5%–8.5%]) were considered abnormal, which includes variants associated with known genomic disorders or variants of possible significance. CMA results were normal in 10 of 852 patients (1.2%) with abnormal karyotype due to balanced rearrangements or unidentified marker chromosome. CMA with whole-genome coverage and CMA with targeted genomic regions detected clinically relevant copy-number changes in 7.3% (51 of 697) and 5.3% (8 of 151) of patients, respectively, both higher than karyotype. With the exception of recurrent deletion and duplication of chromosome 16p11.2 and 15q13.2q13.3, most copy-number changes were unique or identified in only a small subset of patients. CONCLUSIONS: CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.

EEG abnormalities and seizures in genetically diagnosed Fragile X syndrome

We describe the seizure and EEG characteristics in a population of children with known Fragile X. The medical records of 135 genetically confirmed FXS patients receiving care in a Fragile X clinic and their available EEG reports were reviewed. The mean age was 5.94 years old including 18 males and 1 female. The mean age was 4–9 years old with an age range of 15 months to 13 years old. Twenty‐two patients (16.3%) in the series had parent‐reported behavior suspicious of seizures. Sixteen patients (14.1%, 1 female) had at least one EEG recorded for evaluation of clinical events suspicious for seizure, and three patients (2.2%) had an EEG in the context of a polysomnography for diagnosing sleep apnea. The mean age at EEG evaluation was 6.0 years (standard deviation 3.8 years). EEG findings included slowing of background rhythm (n = 9) and epileptiform discharges (n = 7). Four patients had normal EEGs (n = 4). Six patients (4.4% of the sample population) were diagnosed with epilepsy by both clinical seizure semiology and documented EEG abnormalities. Thirteen patients (68.4% of total) had episodes of staring and behavioral arrest with no EEG correlate, indicating non‐epileptic events. Of the eight patients who underwent a repeat EEG, five patients had showed normalization in the posterior dominant rhythm over time, two patients had unchanged findings and one patient had worsening of his EEG. Our data warrant further prospective validation.

De novo mutations in CSNK2A1 are associated with neurodevelopmental abnormalities and dysmorphic features

Whole exome sequencing (WES) can be used to efficiently identify de novo genetic variants associated with genetically heterogeneous conditions including intellectual disabilities. We have performed WES for 4102 (1847 female; 2255 male) intellectual disability/developmental delay cases and we report five patients with a neurodevelopmental disorder associated with developmental delay, intellectual disability, behavioral problems, hypotonia, speech problems, microcephaly, pachygyria and dysmorphic features in whom we have identified de novo missense and canonical splice site mutations in CSNK2A1, the gene encoding CK2α, the catalytic subunit of protein kinase CK2, a ubiquitous serine/threonine kinase composed of two regulatory (β) and two catalytic (α and/or α′) subunits. Somatic mutations in CSNK2A1 have been implicated in various cancers; however, this is the first study to describe a human condition associated with germline mutations in any of the CK2 subunits.

BRAT1 mutations present with a spectrum of clinical severity

Mutations in BRAT1, encoding BRCA1‐associated ATM activator 1, are associated with a severe phenotype known as rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL; OMIM # 614498), characterized by intractable seizures, hypertonia, autonomic instability, and early death. We expand the phenotypic spectrum of BRAT1 related disorders by reporting on four individuals with various BRAT1 mutations resulting in clinical severity that is either mild or moderate compared to the severe phenotype seen in RMFSL. Representing mild severity are three individuals (Patients 1–3), who are girls (including two sisters, Patients 1–2) between 4 and 10 years old, with subtle dysmorphisms, intellectual disability, ataxia or dyspraxia, and cerebellar atrophy on brain MRI; additionally, Patient 3 has well‐controlled epilepsy and microcephaly. Representing moderate severity is a 15‐month‐old boy (Patient 4) with severe global developmental delay, refractory epilepsy, microcephaly, spasticity, hyperkinetic movements, dysautonomia, and chronic lung disease. In contrast to RMFSL, his seizure onset occurred later at 4 months of age, and he is still alive. All four of the individuals have compound heterozygous BRAT1 mutations discovered via whole exome sequencing: c.638dupA (p.Val214Glyfs*189); c.803+1G>C (splice site mutation) in Patients 1–2; c.638dupA (p.Val214Glyfs*189); c.419T>C (p.Leu140Pro) in Patient 3; and c.171delG (p.Glu57Aspfs*7); c.419T>C (p.Leu140Pro) in Patient 4. Only the c.638dupA (p.Val214Glyfs*189) mutation has been previously reported in association with RMFSL. These patients illustrate that, compared with RMFSL, BRAT1 mutations can result in both moderately severe presentations evident by later‐onset epilepsy and survival past infancy, as well as milder presentations that include intellectual disability, ataxia/dyspraxia, and cerebellar atrophy.

Advances in Genetic Discovery and Implications for Counseling of Patients and Families with Autism Spectrum Disorders

The prevalence of autism spectrum disorders (ASD) continues to increase. Genetic factors play an important role in the etiology of ASD, although specific genetic causes are identified in only a minority of cases. Recent advances have accelerated the discovery of genes implicated in ASD through convergent genomic analysis of genome-wide association studies, chromosomal microarray, exome sequencing, genome sequencing, and gene networks. Hundreds of candidate genes for ASD have been reported, yet only a handful have proven causative. Symptoms are complex and highly variable, and most cases are likely due to cumulative genetic factors, the interactions among them, as well as environmental factors. Here we summarize recent findings in genomic research regarding discovery of candidate genes, describe the major molecular processes in neural development that may be disrupted in ASD, and discuss the implication of research findings in clinical genetic diagnostic testing and counseling. Continued advances in genetic research will eventually translate into innovative approaches to prevention and treatment of ASD.

Prognostic dilemmas and genetic counseling for prenatally detected fragile X gene expansions.

With widespread adoption of fragile X carrier screening in pregnant women, the number of expectant couples receiving news of an unanticipated Fragile X Mental Retardation 1 (FMR1) gene expansion has increased. The most common abnormal result from maternal FMR1 testing involves an intermediate allele, also known as a gray zone result, which requires genetic counseling but poses minimal risk for an adverse developmental outcome. By contrast, the finding of a maternal FMR1 premutation or full mutation during pregnancy has important implications for the woman herself, her unborn child, and her extended family. These multiple levels of impact, in addition to the complex inheritance pattern and variable expressivity of fragile X‐associated disorders, cause significant stress for newly identified expectant couples and pose unique challenges for genetic counselors in the prenatal setting.

Sex Education and Intellectual Disability: Practices and Insight from Pediatric Genetic Counselors

Intellectual disability (ID) with or without other anomalies is a common referral for genetic counseling. Sessions may include discussions of reproductive implications and other issues related to sex education. Patients with ID regularly meet barriers when trying to obtain sex education due to the misperceptions of others as being either asexual or that such education would promote inappropriate sexual behavior. In this pilot study, we surveyed genetic counselors to explore their experiences with being asked to provide sex education counseling and their comfort in doing so for patients with ID ages 9–17. Results were analyzed from 38 respondents. Caregivers and patients most frequently requested information on puberty, sex abuse prevention, and reproductive health. Genetic counselors were most comfortable when they could provide sex education counseling within the context of a particular condition or constellation of features. They were least comfortable when they lacked familiarity with the patient, caregiver, or the family’s culture. The most frequently cited barriers that prevented genetic counselors from providing sex education counseling were lack of time, lack of training, the patient’s ID being too profound, and a belief that genetic counselors should not be responsible for providing sex education counseling. While many respondents reported that providing sex education counseling is not considered within the scope of a genetic counselor’s practice, they also noted that patients’ families initiate discussions for which counselors should be prepared. Respondents indicated that resource guides specifically designed for use by genetic counselors would be beneficial to their practice. Genetic counselors have the opportunity to embrace the role of advocate and broach the issue of sexual health with caregivers and patients by directing them toward educational resources, if not providing sex education directly to effectively serve the needs of patients and caregivers.

FORWARD: A Registry and Longitudinal Clinical Database to Study Fragile X Syndrome

BACKGROUND AND OBJECTIVE: Advances in the care of patients with fragile X syndrome (FXS) have been hampered by lack of data. This deficiency has produced fragmentary knowledge regarding the natural history of this condition, healthcare needs, and the effects of the disease on caregivers. To remedy this deficiency, the Fragile X Clinic and Research Consortium was established to facilitate research. Through a collective effort, the Fragile X Clinic and Research Consortium developed the Fragile X Online Registry With Accessible Research Database (FORWARD) to facilitate multisite data collection. This report describes FORWARD and the way it can be used to improve health and quality of life of FXS patients and their relatives and caregivers. METHODS: FORWARD collects demographic information on individuals with FXS and their family members (affected and unaffected) through a 1-time registry form. The longitudinal database collects clinician- and parent-reported data on individuals diagnosed with FXS, focused on those who are 0 to 24 years of age, although individuals of any age can participate. RESULTS: The registry includes >2300 registrants (data collected September 7, 2009 to August 31, 2014). The longitudinal database includes data on 713 individuals diagnosed with FXS (data collected September 7, 2012 to August 31, 2014). Longitudinal data continue to be collected on enrolled patients along with baseline data on new patients. CONCLUSIONS: FORWARD represents the largest resource of clinical and demographic data for the FXS population in the United States. These data can be used to advance our understanding of FXS: the impact of cooccurring conditions, the impact on the day-to-day lives of individuals living with FXS and their families, and short-term and long-term outcomes.

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs.

Understanding Adult Participant and Parent Empowerment Prior to Evaluation in the Undiagnosed Diseases Network

The burden of living with an undiagnosed condition is high and includes physical and emotional suffering, frustrations, and uncertainty. For patients and families experiencing these stressors, higher levels of empowerment may be associated with better outcomes. Thus, it is important to understand the experiences of patients with undiagnosed conditions and their families affected by undiagnosed conditions in order to identify strategies for fostering empowerment. In this study, we used the Genetic Counseling Outcome Scale (GCOS-24) to assess levels of empowerment and support group participation in 35 adult participants and 67 parents of child participants in the Undiagnosed Diseases Network (UDN) prior to their UDN in-person evaluation. Our results revealed significantly lower empowerment scores on the GCOS-24 in adult participants compared to parents of child participants [t(100) = − 3.01, p = 0.003, average difference = − 11.12, 95% CI (− 3.78, − 18.46)] and no significant association between support group participation and empowerment scores. The majority of participants (84.3%, 86/102) are not currently participating in any support groups, and participation rates were not significantly different for adult participants and parents of child participants (11.4 vs. 19.7%, respectively, FE p = 0.40). Open-ended responses provided additional insight into support group participation, the challenges of living with undiagnosed conditions, and positive coping strategies. Future research will evaluate the extent to which empowerment scores change as participation in the UDN unfolds.