Background Primary immunodeficiency diseases (PIDDs) are inherited disorders of the immune system. The most severe form, severe combined immunodeficiency (SCID), presents with profound deficiencies ...of T cells, B cells, or both at birth. If not treated promptly, affected patients usually do not live beyond infancy because of infections. Genetic heterogeneity of SCID frequently delays the diagnosis; a specific diagnosis is crucial for life-saving treatment and optimal management. Objective We developed a next-generation sequencing (NGS)–based multigene-targeted panel for SCID and other severe PIDDs requiring rapid therapeutic actions in a clinical laboratory setting. Methods The target gene capture/NGS assay provides an average read depth of approximately 1000×. The deep coverage facilitates simultaneous detection of single nucleotide variants and exonic copy number variants in one comprehensive assessment. Exons with insufficient coverage (<20× read depth) or high sequence homology (pseudogenes) are complemented by amplicon-based sequencing with specific primers to ensure 100% coverage of all targeted regions. Results Analysis of 20 patient samples with low T-cell receptor excision circle numbers on newborn screening or a positive family history or clinical suspicion of SCID or other severe PIDD identified deleterious mutations in 14 of them. Identified pathogenic variants included both single nucleotide variants and exonic copy number variants, such as hemizygous nonsense, frameshift, and missense changes in IL2RG ; compound heterozygous changes in ATM , RAG1 , and CIITA ; homozygous changes in DCLRE1C and IL7R ; and a heterozygous nonsense mutation in CHD7. Conclusion High-throughput deep sequencing analysis with complete clinical validation greatly increases the diagnostic yield of severe primary immunodeficiency. Establishing a molecular diagnosis enables early immune reconstitution through prompt therapeutic intervention and guides management for improved long-term quality of life.
Abstract Background Familial involvement is common in dilated cardiomyopathy (DCM) and >40 genes have been implicated in causing disease. However, the role of genetic testing in clinical practice is ...not well defined. We examined the experience of clinical genetic testing in a diverse DCM population to characterize the prevalence and predictors of gene mutations. Methods and Results We studied 264 unrelated adult and pediatric DCM index patients referred to 1 reference lab for clinical genetic testing. Up to 10 genes were analyzed ( MYH7 , TNNT2 , TNNI3 , TPM1 , MYBPC3 , ACTC , LMNA , PLN , TAZ , and LDB3 ), and 70% of patients were tested for all genes. The mean age was 26.6 ± 21.3 years, and 52% had a family history of DCM. Rigorous criteria were used to classify DNA variants as clinically relevant (mutations), variants of unknown clinical significance (VUS), or presumed benign. Mutations were found in 17.4% of patients, commonly involving MYH7 , LMNA , or TNNT2 (78%). An additional 10.6% of patients had VUS. Genetic testing was rarely positive in older patients without a family history of DCM. Conversely in pediatric patients, family history did not increase the sensitivity of genetic testing. Conclusions Using rigorous criteria for classifying DNA variants, mutations were identified in 17% of a diverse group of DCM index patients referred for clinical genetic testing. The low sensitivity of genetic testing in DCM reflects limitations in both current methodology and knowledge of DCM-associated genes. However, if mutations are identified, genetic testing can help guide family management.
Genetic Evaluation of Autism Mendelsohn, Nancy J., MD; Schaefer, G. Bradley, MD
Seminars in pediatric neurology,
03/2008, Letnik:
15, Številka:
1
Journal Article
Recenzirano
The autism spectrum disorders represent a collective of neurogenetic conditions that have in common altered socialization and communication. Much attention has been given lately to the marked ...increased in the reported incidence of these conditions. Significant debate also exists as to the basis of the reported increase. Regardless, clinical geneticists and pediatric neurologists alike are seeing a tremendous increase in the number of referrals for autism and related conditions. Continuing advances in genetic testing provide a moving target for the clinician in determining an appropriate diagnostic plan. In this article, we review the most recent advances in genetic testing technology and their potential application to the etiologic evaluation of patients with autism spectrum disorders.
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