Genomic disorders in the genomics era

AbstractCongenital heart disease (CHD), the most common major congenital anomaly, is associated with a genetic syndrome (chromosomal anomalies, genomic disorders, or monogenic disease) in 30% of patients. The aim of this systematic review is to evaluate if, in the neonatal setting, clinical clues that orient the diagnostic path can be identified. For this purpose, we revised the most frequent dysmorphic features described in newborns with CHD, comparing those associated with monogenic syndromes (MSG) with the ones reported in newborns with genomic disorders. For this systematic review according to PRISMA statement, we used PubMed, Medline, Google Scholar, Scopus database, and search terms related to CHD and syndrome. We found a wide range of dysmorphisms (ocular region, ears, mouth, and/or palate and phalangeal anomalies) detected in more than half of MSGs were found to be associated with CHDs, but those anomalies are also described in genomic rearrangements syndromes with equal prevalence. These findings confirm that etiological diagnosis in newborns is challenging, and only the prompt and expert recognition of features suggestive of genetic conditions can improve the selection of appropriate, cost-effective diagnostic tests. However, in general practice, it is crucial to recognize clues that can suggest the presence of a genetic syndrome, and neonatologists often have the unique opportunity to be the first to identify abnormalities in the neonate.

Download Full-text

Genomic Basis of Aromatase Excess Syndrome: Recombination- and Replication-Mediated Rearrangements Leading to CYP19A1 Overexpression

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2013-2520 ◽

2013 ◽

Vol 98 (12) ◽

pp. E2013-E2021 ◽

Cited By ~ 14

Author(s):

Maki Fukami ◽

Takayoshi Tsuchiya ◽

Heike Vollbach ◽

Kristy A. Brown ◽

Shuji Abe ◽

...

Keyword(s):

Gc Content ◽

Replication Timing ◽

Nonhomologous End Joining ◽

Coding Region ◽

End Joining ◽

Clinical Consequences ◽

Underlying Mechanisms ◽

Nonallelic Homologous Recombination ◽

Genomic Disorders ◽

Flanking Regions

Context: Genomic rearrangements at 15q21 have been shown to cause overexpression of CYP19A1 and resultant aromatase excess syndrome (AEXS). However, mutation spectrum, clinical consequences, and underlying mechanisms of these rearrangements remain to be elucidated. Objective: The aim of the study was to clarify such unsolved matters. Design, Setting, and Methods: We characterized six new rearrangements and investigated clinical outcome and local genomic environments of these rearrangements and of three previously reported duplications/deletions. Results: Novel rearrangements included simple duplication involving exons 1–10 of CYP19A1 and simple and complex rearrangements that presumably generated chimeric genes consisting of the coding region of CYP19A1 and promoter-associated exons of neighboring genes. Clinical severities were primarily determined by the copy number of CYP19A1 and the property of the fused promoters. Sequences at the fusion junctions suggested nonallelic homologous recombination, nonhomologous end-joining, and replication-based errors as the underlying mechanisms. The breakpoint-flanking regions were not enriched with GC content, palindromes, noncanonical DNA structures, or known rearrangement-associated motifs. The rearrangements resided in early-replicating segments. Conclusions: These results indicate that AEXS is caused by duplications involving CYP19A1 and simple and complex rearrangements that presumably lead to the usage of cryptic promoters of several neighboring genes. Our data support the notion that phenotypes depend on the dosage of CYP19A1 and the characteristics of the fused promoters. Furthermore, we show that the rearrangements in AEXS are generated by both recombination- and replication-mediated mechanisms, independent of the known rearrangement-inducing DNA features or late-replication timing. Thus, AEXS represents a unique model for human genomic disorders.

Download Full-text

Information and genetic counselling for psychiatric risks in children with rare genomic disorders

10.1101/19007294 ◽

2019 ◽

Author(s):

Andrew Cuthbert ◽

Aimee Challenger ◽

Jeremy Hall ◽

Marianne BM van den Bree

Keyword(s):

Genetic Counselling ◽

Online Survey ◽

Genomic Medicine ◽

Genetic Diagnosis ◽

Single Nucleotide Variants ◽

Full Spectrum ◽

Face To Face ◽

Professional Information ◽

Genomic Disorders ◽

Psychiatric Manifestations

AbstractPurposeGenomic medicine has transformed the diagnosis of neurodevelopmental disorders. Evidence of increased psychiatric comorbidity associated with genomic copy number and single nucleotide variants (CNV and SNV) may not be fully considered when providing genetic counselling. We explored parents’ experiences of genetics services and how they obtained information concerning psychiatric manifestations.MethodsParents of children diagnosed with genomic variants completed an online survey exploring, (i) how they experienced the genetic diagnosis, and (ii) how they acquired information about psychiatric, developmental and physical manifestations.ResultsTwo-hundred and 86 respondents completed the survey. Thirty percent were unsatisfied with receiving genetic diagnoses. Satisfaction was predicted if communication was by geneticists (p = 0.004); provided face-to-face (p = 0.003); clearly explained (p < 0.001); and accompanied by support (p = 0.017). Parents obtained psychiatric information from non-professional sources more often than developmental (ϕ 0.26, p < 0.001) and physical manifestations (ϕ 0.21, p = 0.003), which mostly came from health professionals. Information from support organisations was more helpful than from geneticists (odds ratio [OR] 21.0, 95% CI 5.1 – 86.8, p < 0.001); paediatricians (OR 11.0, 1.4 – 85.2, p = 0.004); and internet sites (OR 15.5, 3.7 – 64.8, p < 0.001).ConclusionA paucity of professional information about psychiatric risks after genetic diagnosis may impede early diagnosis and intervention for children with high genotypic risks. Planned integration of genomic testing into mainstream services should include genetic counselling training to address the full spectrum of developmental, physical and psychiatric manifestations and timely provision of high-quality information.

Download Full-text

What Have Studies of Genomic Disorders Taught Us About Our Genome?

Methods in Molecular Biology - Genomic Structural Variants ◽

10.1007/978-1-61779-507-7_1 ◽

2011 ◽

pp. 1-27 ◽

Cited By ~ 11

Author(s):

Alexandra D. Simmons ◽

Claudia M. B. Carvalho ◽

James R. Lupski

Keyword(s):

Genomic Disorders

Download Full-text

A novel 14q13.1–21.1 deletion identified by CNV-Seq in a patient with brain-lung-thyroid syndrome, tooth agenesis and immunodeficiency

Molecular Cytogenetics ◽

10.1186/s13039-019-0463-z ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Xuyun Hu ◽

Jun Liu ◽

Ruolan Guo ◽

Jun Guo ◽

Zhipeng Zhao ◽

...

Keyword(s):

De Novo ◽

Deletion Syndrome ◽

Tooth Agenesis ◽

Diagnostic Strategy ◽

Genomic Disorder ◽

Case Presentation ◽

Whole Exome ◽

Number Variation ◽

Phenotype Heterogeneity ◽

Genomic Disorders

Abstract Background Chromosome 14q11-q22 deletion syndrome (OMIM 613457) is a rare genomic disorder. The phenotype heterogeneity depends on the deletion size, breakpoints and genes deleted. Critical genes like FOXG1, NKX2–1, PAX9 were identified. Case presentation We performed whole exome sequencing (WES) and copy number variation sequencing (CNV-seq) for a patient with mild speech and motor developmental delay, short stature, recurrent pulmonary infections, tooth agenesis and triad of brain-lung-thyroid syndrome. By using CNV-seq, we identified a 3.1 Mb de novo interstitial deletion of the 14q13.2q21.1 region encompassing 17 OMIM genes including NKX2–1, PAX9 and NFKBIA. Our patient’s phenotype is consistent with other published 14q13 deletion patients. Conclusion Our results showed the combination of WES and CNV-seq is an effective diagnostic strategy for patients with genetic or genomic disorders. After reviewing published patients, we also proposed a new critical region for 14q13 deletion syndrome with is a more benign disorder compared to 14q11-q22 deletion syndrome.

Download Full-text

Electrochemical (Bio)Sensing of Maple Syrup Urine Disease Biomarkers Pointing to Early Diagnosis: A Review

Applied Sciences ◽

10.3390/app10207023 ◽

2020 ◽

Vol 10 (20) ◽

pp. 7023

Author(s):

Sophia Karastogianni ◽

Stella Girousi

Keyword(s):

Maple Syrup Urine Disease ◽

Point Mutations ◽

Branched Chain Amino Acids ◽

Genetic Defects ◽

Maple Syrup ◽

Disease Biomarkers ◽

Neurocognitive Dysfunctions ◽

Urine Disease ◽

Branched Chain ◽

Genomic Disorders

Metabolic errors are inherited diseases, where genetic defects prevent a metabolic path, ending up in enzyme malfunction. In correspondence to its remaining or plenitude fall of enzymatic potency, there is an amassment of dangerous metabolites near the metabolic bar and/or a dearth of necessary products, inducing a certain disease. These metabolic errors may include deviations such as point mutations, expunctions or interferences, or further complicated genomic disorders. Based on these facts, maple syrup urine disease (MSUD) is a scarce metabolic disease, generated by huge concentrations of branched-chain amino acids (b AAs), i.e., leucine, isoleucine, and valine. In this situation, these large amounts of b AAs provoke abnormalities such as liver failure, neurocognitive dysfunctions, and probably death. To overpass those problems, it is crucial to implement a timely and agile diagnosis at the early stages of life in view of their immutable consequence on neonates. Thus, this review will describe MSUD and b AAs analysis based on electrochemical (bio)sensing.

Download Full-text