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In children undergoing genetic testing for physical health concerns, we examined how often the results also revealed information about their risk for neurodevelopmental disorders. The study sample consisted of 3056 genetic tests (1686 chromosomal microarrays--CMAs, and 1378 next-generation sequencing--NGS panels) ordered at a tertiary pediatric hospital because of a physical/congenital health problem. Tests ordered to investigate developmental concerns were excluded. Pathogenic, or likely pathogenic variants were manually reviewed for diagnostic likelihood, and for evidence of an association with a neurodevelopmental disorder (e.g., autism or intellectual disability). A total of 169 CMAs (10%) and 232 NGS panels (17%) had likely diagnostic results. More than half (52%) of all diagnostic results had established evidence of a neurodevelopmental disorder association. In summary, there is a high prevalence of neurodevelopmental implications from genetic tests ordered for physical/congenital indications. This broad clinical utility suggests a growing need for genetics-first developmental care pathways.

The widespread availability of comparative genomic hybridization (CGH) array analysis has led to the discovery of several genomic microdeletion-associated syndromes and has identified possible genetic causes for patients with previously unexplained clinical features. We report the case of four unrelated patients who share common clinical characteristics, namely failure to thrive, developmental delay, dysmorphic features, and congenital anomalies. CGH array analysis revealed that all four patients had a de novo microdeletion at 16q22.1. In this case report, we describe the clinical features of these patients and offer possible explanations for how their 16q22.1 microdeletion may account for their symptoms. We also suggest guidelines for the management of 16q22.1 microdeletion based on the phenotypes seen in our patients and the function of the genes affected by this microdeletion.

The introduction of diagnostic clinical genome and exome sequencing (CGES) is changing the scope of practice for clinical geneticists. Many large institutions are making a significant investment in infrastructure and technology, allowing clinicians to access CGES, especially as health-care coverage begins to extend to clinically indicated genomic sequencing-based tests. Translating and realizing the comprehensive clinical benefits of genomic medicine remain a key challenge for the current and future care of patients. With the increasing application of CGES, it is necessary for geneticists and other health-care providers to understand its benefits and limitations in order to interpret the clinical relevance of genomic variants identified in the context of health and disease. New, collaborative working relationships with specialists across diverse disciplines (e.g., clinicians, laboratorians, bioinformaticians) will undoubtedly be key attributes of the future practice of clinical genetics and may serve as an example for other specialties in medicine. These new skills and relationships will also inform the development of the future model of clinical genetics training curricula. To address the evolving role of the clinical geneticist in the rapidly changing climate of genomic medicine, two Clinical Genetics Think Tank meetings were held that brought together physicians, laboratorians, scientists, genetic counselors, trainees, and patients with experience in clinical genetics, genetic diagnostics, and genetics education. This article provides recommendations that will guide the integration of genomics into clinical practice.Genet Med 18 11, 1075-1084.

Key Points Question What is the diagnostic yield of genome sequencing in children with unexplained medical complexity and prior negative results of genetic testing? Findings In this cohort study that included 138 individuals from 49 families, genome sequencing detected all genomic variation previously identified by conventional genetic testing and resulted in a new diagnosis for 31% of patients. Meaning This study suggests that, because of its high yield, comprehensive nature, and increasingly competitive costs, genome sequencing is a potentially first-tier genetic test for children with unexplained medical complexity., Importance Children with medical complexity (CMC) represent a growing population in the pediatric health care system, with high resource use and associated health care costs. A genetic diagnosis can inform prognosis, anticipatory care, management, and reproductive planning. Conventional genetic testing strategies for CMC are often costly, time consuming, and ultimately unsuccessful. Objective To evaluate the analytical and clinical validity of genome sequencing as a comprehensive diagnostic genetic test for CMC. Design, Setting, and Participants In this cohort study of the prospective use of genome sequencing and comparison with standard-of-care genetic testing, CMC were recruited from May 1, 2017, to November 30, 2018, from a structured complex care program based at a tertiary care pediatric hospital in Toronto, Canada. Recruited CMC had at least 1 chronic condition, technology dependence (child is dependent at least part of each day on mechanical ventilators, and/or child requires prolonged intravenous administration of nutritional substances or drugs, and/or child is expected to have prolonged dependence on other device-based support), multiple subspecialist involvement, and substantial health care use. Review of the care plans for 545 CMC identified 143 suspected of having an undiagnosed genetic condition. Fifty-four families met inclusion criteria and were interested in participating, and 49 completed the study. Probands, similarly affected siblings, and biological parents were eligible for genome sequencing. Exposures Genome sequencing was performed using blood-derived DNA from probands and family members using established methods and a bioinformatics pipeline for clinical genome annotation. Main Outcomes and Measures The primary study outcome was the diagnostic yield of genome sequencing (proportion of CMC for whom the test result yielded a new diagnosis). Results Genome sequencing was performed for 138 individuals from 49 families of CMC (29 male and 20 female probands; mean [SD] age, 7.0 [4.5] years). Genome sequencing detected all genomic variation previously identified by conventional genetic testing. A total of 15 probands (30.6%; 95% CI 19.5%-44.6%) received a new primary molecular genetic diagnosis after genome sequencing. Three individuals had novel diseases and an additional 9 had either ultrarare genetic conditions or rare genetic conditions with atypical features. At least 11 families received diagnostic information that had clinical management implications beyond genetic and reproductive counseling. Conclusions and Relevance This study suggests that genome sequencing has high analytical and clinical validity and can result in new diagnoses in CMC even in the setting of extensive prior investigations. This clinical population may be enriched for ultrarare and novel genetic disorders. Genome sequencing is a potentially first-tier genetic test for CMC., This cohort study evaluates the analytical and clinical validity of genome sequencing as a comprehensive diagnostic genetic test for children with medical complexity.

The clinical use of whole-genome sequencing (WGS) is expected to alter pediatric medical management. The study aimed to describe the type and cost of healthcare activities following pediatric WGS compared to chromosome microarray (CMA). Healthcare activities prompted by WGS and CMA were ascertained for 101 children with developmental delay over 1 year. Activities following receipt of non-diagnostic CMA were compared to WGS diagnostic and non-diagnostic results. Activities were costed in 2016 Canadian dollars (CDN). Ongoing care accounted for 88.6% of post-test activities. The mean number of lab tests was greater following CMA than WGS (0.55 vs. 0.09; p = 0.007). The mean number of specialist visits was greater following WGS than CMA (0.41 vs. 0; p = 0.016). WGS results (diagnostic vs. non-diagnostic) modified the effect of test type on mean number of activities (p

Importance Copy number variation (CNV) is an important cause of neuropsychiatric disorders. Little is known about the role of CNV in adults with epilepsy and intellectual disability. Objectives To evaluate the prevalence of pathogenic CNVs and identify possible candidate CNVs and genes in patients with epilepsy and intellectual disability. Design, Setting, and Participants In this cross-sectional study, genome-wide microarray was used to evaluate a cohort of 143 adults with unexplained childhood-onset epilepsy and intellectual disability who were recruited from the Toronto Western Hospital epilepsy outpatient clinic from January 1, 2012, through December 31, 2014. The inclusion criteria were (1) pediatric seizure onset with ongoing seizure activity in adulthood, (2) intellectual disability of any degree, and (3) no structural brain abnormalities or metabolic conditions that could explain the seizures. Main Outcomes and Measures DNA screening was performed using genome-wide microarray platforms. Pathogenicity of CNVs was assessed based on the American College of Medical Genetics guidelines. The Residual Variation Intolerance Score was used to evaluate genes within the identified CNVs that could play a role in each patient’s phenotype. Results Of the 2335 patients, 143 probands were investigated (mean [SD] age, 24.6 [10.8] years; 69 male and 74 female). Twenty-three probands (16.1%) and 4 affected relatives (2.8%) (mean [SD] age, 24.1 [6.1] years; 11 male and 16 female) presented with pathogenic or likely pathogenic CNVs (0.08-18.9 Mb). Five of the 23 probands with positive results (21.7%) had more than 1 CNV reported. Parental testing revealed de novo CNVs in 11 (47.8%), with CNVs inherited from a parent in 4 probands (17.4%). Sixteen of 23 probands (69.6%) presented with previously cataloged human genetic disorders and/or defined CNV hot spots in epilepsy. Eight nonrecurrent rare CNVs that overlapped 1 or more genes associated with intellectual disability, autism, and/or epilepsy were identified: 2p16.1-p15 duplication, 6p25.3-p25.1 duplication, 8p23.3p23.1 deletion, 9p24.3-p23 deletion, 10q11.22-q11.23 duplication, 12p13.33-13.2 duplication, 13q34 deletion, and 16p13.2 duplication. Five genes are of particular interest given their potential pathogenicity in the corresponding phenotypes and least tolerability to variation:ABAT, KIAA2022,COL4A1, CACNA1C,andSMARCA2.ABATduplication was associated with Lennox-Gastaut syndrome andKIAA2022deletion with Jeavons syndrome. Conclusions and Relevance The high prevalence of pathogenic CNVs in this study highlights the importance of microarray analysis in adults with unexplained childhood-onset epilepsy and intellectual disability. Additional studies and comparison with similar cases are required to evaluate the effects of deletions and duplications that overlap specific genes.

Item does not contain fulltext Copy number variations associated with abnormal gene dosage have an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID) and autism. We hypothesize that the chromosome 2q23.1 region encompassing MBD5 is a dosage-dependent region, wherein deletion or duplication results in altered gene dosage. We previously established the 2q23.1 microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications, thus establishing a complementary duplication syndrome. The observed phenotype includes ID, language impairments, infantile hypotonia and gross motor delay, behavioral problems, autistic features, dysmorphic facial features (pinnae anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and minor digital anomalies (fifth finger clinodactyly and large broad first toe). The microduplication size varies among all cases and ranges from 68 kb to 53.7 Mb, encompassing a region that includes MBD5, an important factor in methylation patterning and epigenetic regulation. We previously reported that haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion syndrome and that mutations in MBD5 are associated with autism. In this study, we demonstrate that MBD5 is the only gene in common among all duplication cases and that overexpression of MBD5 is likely responsible for the core clinical features present in 2q23.1 microduplication syndrome. Phenotypic analyses suggest that 2q23.1 duplication results in a slightly less severe phenotype than the reciprocal deletion. The features associated with a deletion, mutation or duplication of MBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development.

Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild-type DNA constructs as well as in silico protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with intellectual disability.

We report on two patients with developmental delay, hypotonia, and autistic features associated with duplications of chromosome region 2q23.1-2q23.2 detected by chromosome microarray analysis. The duplications include one OMIM Morbid Map gene, MBD5, as well as seven known RefSeq genes (ACVR2A, ORC4L, EPC2, KIF5C, MIR1978, LYPD6B, and LYPD6). MBD5 lies in the minimum area of overlap of the 2q23.1 microdeletion syndrome. This report provides the first detailed clinical examination of two individuals with a duplication of this region and suggests that brain development and cognitive function may be affected by an increased dosage of the genes involved. © 2012 Macmillan Publishers Limited All rights reserved., link_to_OA_fulltext

Background Agenesis of the corpus callosum (ACC) is a rare congenital anomaly presenting with partial or complete absence of the corpus callosum (CC). ACC could present as an isolated finding or a part of a genetic syndrome. A recent publication reported two cases of mal-development of CC in two unrelated individuals with posterior polymorphous corneal dystrophy (PPCD), an autosomal dominant inherited disorder of the corneal endothelium. Both cases presented novel deletions of the ZEB1 gene. *ZEB1 mutations are reported in approximately one third of PPCD patients. Objective To report a case of a child with ACC and de novo chromosome 10 deletion involving ZEB1 gene. Case report: a 12-year-old girl presented with facial dysmorphism, bilateral renal reflux, developmental delay, autism and ACC. She presented with normal growth parameters, continued to acquire new developmental skills with no regression episodes or seizures. Ophthalmological exam showed thinning of the retinal nerve fibre layer in the nasal aspect around the discs with relative sparing of the macular areas bilaterally. The rest of the ocular examination, including corneal exam was normal. Results Whole genome sequencing revealed heterozygous de novo deletion in chromosome 10p11.23- p11.22 (del:chr10:30814000–32892000) overlapping ZEB1 gene. Conclusion This is the third case reported of ZEB1 gene deletion in a patient with CC anomalies, and the first patient with no corneal anomalies but with autism. This finding might imply a broader phenotypic range for ZEB1 deletion than previously thought and add it to the possible causes of autism.

Intellectual disability (ID) affects 1%–3% of the population. While it has a strong genetic component, finding a genetic diagnosis remains challenging. Given the high rate of de novo events in ID, family-based sequencing may be an important tool. In 2012 Schuurs-Hoeijmakers et al ., reported two children with ID and characteristic features associated with a heterozygote mutation in PACS1. We report the same mutation elucidated by whole exome sequencing (WES) in two additional children. Patient 1 was born at term to a 30-year-old primigravida from Bangladesh. Her birth weight and length were 3–10th% and head circumference 50–75th%. ID presented in the first year of life. She had sparse hair, a high forehead, frontal bossing, hypertelorism, deep-set eyes, a broad nasal root, full lips and a wide mouth. She had marked hypotonia, decreased muscle bulk and hyperextensible joints. WES revealed a PACS1 mutation. (NM_018026)exon4:c. C607T:p. R203W. Patient 2 was born at term to a 34-year-old primigravida from China. Birth weight and length were 10–25th% and head circumference 25–50th%. At birth, an anoplasty was performed for an ectopic anus. A right duplex kidney and undescended testes were identified. ID presented before age one. He had a short forehead, bushy eyebrows, short nose, large mouth, uplifting earlobes, bilateral single palmar creases, widely spaced nipples and an umbilical hernia. WES revealed the same mutation. Our two cases highlight the clinical utility of WES in helping establish a diagnosis of an unfamiliar clinical syndrome and supports the discovery of a now recognisable syndrome due to mutation in PACS1.