SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile

PurposeThis study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants.MethodsIndividuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope.ResultsWe reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies.ConclusionSOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies.     

Novel GNB1 de novo mutation in a patient with neurodevelopmental disorder and cutaneous mastocytosis: Clinical report and literature review

De novo monoallelic mutations in the GNB1 gene, encoding a β subunit of heterotrimeric G proteins, cause a newly recognized disorder with the typical clinical picture of severe developmental delay/intellectual disability, hypotonia and extrapyramidal symptoms. We describe another case of the condition with manifestations of cutaneous mastocytosis associated with a novel do novo mutation GNB1NM_001282539.1: c.230G > T; p.(Gly77Val). We also present the detailed clinical and etiopathogenetic discussion on previously diagnosed patients as well as suggestions for the link of the mutation with skin disease.     

Perspectives and preferences regarding genomic secondary findings in underrepresented prenatal and pediatric populations: A mixed-methods approach

PurposePatients undergoing clinical exome sequencing (ES) are routinely offered the option to receive secondary findings (SF). However, little is known about the views of individuals from underrepresented minority pediatric or prenatal populations regarding SF.MethodsWe explored the preferences for receiving hypothetical categories of SF (H-SF) and reasons for accepting or declining actual SF through surveying (n = 149) and/or interviewing (n = 47) 190 families undergoing pediatric or prenatal ES.ResultsUnderrepresented minorities made up 75% of the probands. In total, 150 families (79%) accepted SF as part of their child/fetus’s ES. Most families (63%) wanted all categories of H-SF. Those who declined SF as part of ES were less likely to want H-SF across all categories. Interview findings indicate that some families did not recall their SF decision. Preparing for the future was a major motivator for accepting SF, and concerns about privacy, discrimination, and psychological effect drove decliners.ConclusionA notable subset of families (37%) did not want at least 1 category of H-SF, suggesting more hesitancy about receiving all available results than previously reported. The lack of recollection of SF decisions suggests a need for alternative communication approaches. Results highlight the importance of the inclusion of diverse populations in genomic research.     

De novo variants in the PABP domain of PABPC1 lead to developmental delay

PurposeThe study aimed to investigate the role of PABPC1 in developmental delay (DD).MethodsChildren were examined by geneticists and pediatricians. Variants were identified using exome sequencing and standard downstream bioinformatics pipelines. We performed in silico molecular modeling and coimmunoprecipitation to test if the variants affect the interaction between PABPC1 and PAIP2. We performed in utero electroporation of mouse embryo brains to enlighten the function of PABPC1.ResultsWe describe 4 probands with an overlapping phenotype of DD, expressive speech delay, and autistic features and heterozygous de novo variants that cluster in the PABP domain of PABPC1. Further symptoms were seizures and behavioral disorders. Molecular modeling predicted that the variants are pathogenic and would lead to decreased binding affinity to messenger RNA metabolism-related proteins, such as PAIP2. Coimmunoprecipitation confirmed this because it showed a significant weakening of the interaction between mutant PABPC1 and PAIP2. Electroporation of mouse embryo brains showed that Pabpc1 knockdown decreases the proliferation of neural progenitor cells. Wild-type Pabpc1 could rescue this disturbance, whereas 3 of the 4 variants did not.ConclusionPathogenic variants in the PABP domain lead to DD, possibly because of interference with the translation initiation and subsequently an impaired neurogenesis in cortical development.     

全基因组外显子测序及其在遗传病研究中的应用

全基因组外显子测序是指利用序列捕获技术将全基因组外显子区域DNA捕捉并富集,然后进行高通量测序的基因组分析方法.与传统测序方式相比,该技术具有耗时短、成本低、通量大,对样品的要求量少等特点,已经成为人们研究某些疾病致病基因的重要方法.此文就全基因组外显子测序的优缺点及其在遗传病中的应用作简要综述.     

Perspectives of United States neonatologists on genetic testing practices

PurposeGenetic disorders often present in the neonatal intensive care unit (NICU), and detecting or confirming these diagnoses has been shown to impact care. However, the availability and use of genetic testing, particularly exome or genome sequencing, among NICUs varies widely. We therefore sought to investigate practice patterns related to genetic testing in NICUs around the country to identify and quantify potential discrepancies.MethodsWe designed a survey that was distributed to neonatologists via email. The survey contained questions related to test availability and desirability, the process of test ordering in NICU, and general comfort with ordering and interpreting genetic testing. Demographic data related to the survey participants and characteristics of their NICU were also obtained.ResultsIn total, 162 neonatologists completed the survey, representing 40 states and 112 distinct NICUs. Although nearly all (93.2%) neonatologists attributed a high level of importance to identifying a genetic diagnosis for their patients, genetic consultations were only available at 78% of NICUs and exome or genome sequencing was not available on a regular basis (69% of NICUs).ConclusionAlthough, among US neonatologists surveyed, most feel that genetic tests are indicated for their patients, these are not always clinically available. Further research into implementation barriers is warranted.     

The patient with 41 reports: Analysis of laboratory exome sequencing reporting of a “virtual patient”

PurposeFew studies have systematically analyzed the structure and content of laboratory exome sequencing reports from the same patient.MethodsWe merged 8 variants from patients into “normal” exomes to create virtual patient–parent trios. We provided laboratories worldwide with the data and patient phenotype information (developmental delay, dysmorphic features, and cardiac hypertrophy). Laboratories analyzed the data and issued a diagnostic exome report. Reports were scored using a coding matrix developed from existing guidelines.ResultsIn total, 41 laboratories representing 17 countries issued reports. Reporting of quality control statistics and technical information was poor (46.3%). Although 75.6% of the reports clearly stated the classification of all reported variants, few reports listed extensive evidence supporting variant classification. Only 53.1% of laboratories that reported unsolicited or secondary findings gave advice regarding health-related follow-up and 20.5% gave advice regarding cascade testing for relatives. Of the 147 variants reported, 105 (71.4%) were classified in agreement with classifications based on American College of Medical Genetics and Genomics/Association for Molecular Pathology and Association for Clinical Genomic Science guidelines. Concordance was higher for known pathogenic variants (86.3%) than for novel unpublished variants (56.8%).ConclusionThe considerable variability identified in the components that laboratories included in their reports and their classification of variants suggests that existing guidelines are not being used consistently with significant implications for patient care.