Authors: Raphael Bernier, Kyle J Steinman, Beau Reilly...

PURPOSE

To characterize the clinical phenotype of the recurrent copy-number variation (CNV) at 1q21.1, we assessed the psychiatric and medical phenotypes of 1q21.1 deletion and duplication carriers ascertained through clinical genetic testing and family member cascade testing, with particular emphasis on dimensional assessment across multiple functional domains.

METHODS

Nineteen individuals with 1q21.1 deletion, 19 individuals with the duplication, and 23 familial controls (noncarrier siblings and parents) spanning early childhood through adulthood were evaluated for psychiatric, neurologic, and other medical diagnoses, and their cognitive, adaptive, language, motor, and neurologic domains were also assessed. Twenty-eight individuals with 1q21.1 CNVs (15 deletion, 13 duplication) underwent structural magnetic resonance brain imaging.

RESULTS

Probands with 1q21.1 CNVs presented with a range of psychiatric, neurologic, and medical disorders. Deletion and duplication carriers shared several features, including borderline cognitive functioning, impaired fine and gross motor functioning, articulation abnormalities, and hypotonia. Increased frequency of Autism Spectrum Disorder (ASD) diagnosis, increased ASD symptom severity, and increased prevalence of macrocephaly were observed in the duplication relative to deletion carriers, whereas reciprocally increased prevalence of microcephaly was observed in the deletion carriers.

CONCLUSIONS

Individuals with 1q21.1 deletions or duplications exhibit consistent deficits on motor and cognitive functioning and abnormalities in head circumference.Genet Med 18 4, 341-349.

Topics: Adult; Child; Child, Preschool; Chromosome Deletion; Chromosome Disorders; Chromosome Duplication; Chromosomes, Human, Pair 1; DNA Copy Number Variations; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Phenotype; Registries; Young Adult

PubMed: 26066539
DOI: 10.1038/gim.2015.78

Review

Authors: Brynn Levy, Ronald Wapner

Chromosomal microarray analysis (CMA) is performed either by array comparative genomic hybridization or by using a single nucleotide polymorphism array. In the prenatal setting, CMA is on par with traditional karyotyping for detection of major chromosomal imbalances such as aneuploidy and unbalanced rearrangements. CMA offers additional diagnostic benefits by revealing sub-microscopic imbalances or copy number variations that are too small to be seen on a standard G-banded chromosome preparation. These submicroscopic imbalances are also referred to as microdeletions and microduplications, particularly when they include specific genomic regions that are associated with clinical sequelae. Not all microdeletions/duplications are associated with adverse clinical phenotypes and in many cases, their presence is benign. In other cases, they are associated with a spectrum of clinical phenotypes that may range from benign to severe, while in some situations, the clinical significance may simply be unknown. These scenarios present a challenge for prenatal diagnosis, and genetic counseling prior to prenatal CMA greatly facilitates delivery of complex results. In prenatal diagnostic samples with a normal karyotype, chromosomal microarray will diagnose a clinically significant subchromosomal deletion or duplication in approximately 1% of structurally normal pregnancies and 6% with a structural anomaly. Pre-test counseling is also necessary to distinguish the primary differences between the benefits, limitations and diagnostic scope of CMA versus the powerful but limited screening nature of non-invasive prenatal diagnosis using cell-free fetal DNA.

Topics: Chromosome Deletion; Chromosome Disorders; Chromosome Duplication; Chromosomes, Human; Comparative Genomic Hybridization; Female; Genetic Counseling; Genetic Predisposition to Disease; Genetic Testing; Humans; Karyotyping; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Predictive Value of Tests; Pregnancy; Prenatal Diagnosis; Reproducibility of Results; Ultrasonography, Prenatal

PubMed: 29447663
DOI: 10.1016/j.fertnstert.2018.01.005

Authors: Maria Teresa Bonati, Chiara Castronovo, Alessandra Sironi...

Both copy number losses and gains occur within subtelomeric 9q34 region without common breakpoints. The microdeletions cause Kleefstra syndrome (KS), whose responsible gene is EHMT1. A 9q34 duplication syndrome (9q34 DS) had been reported in literature, but it has never been characterized by a detailed molecular analysis of the gene content and endpoints. To the best of our knowledge, we report on the first patient carrying the smallest 9q34.3 duplication containing EHMT1 as the only relevant gene. We compared him with 21 reported patients described here as carrying 9q34.3 duplications encompassing the entire gene and extending within ~ 3 Mb. By surveying the available clinical and molecular cytogenetic data, we were able to discover that similar neurodevelopmental disorders (NDDs) were shared by patient carriers of even very differently sized duplications. Moreover, some facial features of the 9q34 DS were more represented than those of KS. However, an accurate in silico analysis of the genes mapped in all the duplications allowed us to support EHMT1 as being sufficient to cause a NDD phenotype. Wider patient cohorts are needed to ascertain whether the rearrangements have full causative role or simply confer the susceptibility to NDDs and possibly to identify the cognitive and behavioral profile associated with the increased dosage of EHMT1.

Topics: Adolescent; Chromosome Duplication; Chromosomes, Human, Pair 9; Comparative Genomic Hybridization; Databases, Factual; Female; France; Gene Dosage; Histone-Lysine N-Methyltransferase; Humans; In Situ Hybridization, Fluorescence; Italy; Male; Molecular Sequence Annotation; Neurodevelopmental Disorders; New Zealand; Oligonucleotide Array Sequence Analysis; Phenotype; Syndrome

PubMed: 31209758
DOI: 10.1007/s10048-019-00581-6

Review

Authors: Priyanka Upadhyai, Eram Fatima Amiri, Vishal Singh Guleria...

The clinical phenotype of 1q21.1 microdeletion syndrome is highly heterogeneous. It is characterized by dysmorphic facial features, microcephaly, and developmental delay. Several congenital defects, including cardiac, ocular, skeletal anomalies, and psychiatric or behavioural abnormalities, have also been described. Here, we report on two siblings with substantial intrafamilial phenotypic variability carrying a heterozygous deletion of the 1q21.1 region spanning a known critical genomic area (~1.35 Mb). The microdeletion was inherited from the unaffected father. Patients described here show a spectrum of clinical features, a portion of which overlap with those previously reported in patients with 1q21.1 microdeletions. In addition, we review the clinical reports of 66 individuals with this condition. These findings extend and substantiate the current clinical understanding of recurrent copy number variations in the 1q21.1 region.

Topics: Abnormalities, Multiple; Adult; Chromosome Deletion; Chromosome Duplication; Chromosomes, Human, Pair 1; DNA Copy Number Variations; Family; Female; Heart Defects, Congenital; Humans; India; Intellectual Disability; Male; Megalencephaly; Microcephaly; Pedigree; Phenotype; Syndrome

PubMed: 32459673
DOI: 10.1097/MCD.0000000000000327

Authors: Jill A Rosenfeld, Ryan N Traylor, G Bradley Schaefer...

Chromosomal band 1q21.1 can be divided into two distinct regions, proximal and distal, based on segmental duplications that mediate recurrent rearrangements. Microdeletions and microduplications of the distal region within 1q21.1, which are susceptibility factors for a variety of neurodevelopmental phenotypes, have been more extensively studied than proximal microdeletions and microduplications. Proximal microdeletions are known as a susceptibility factor for thrombocytopenia-absent radius (TAR) syndrome, but it is unclear if these proximal microdeletions have other phenotypic consequences. Therefore, to elucidate the clinical significance of rearrangements of the proximal 1q21.1 region, we evaluated the phenotypes in patients identified with 1q21.1 rearrangements after referral for clinical microarray testing. We report clinical information for 55 probands with copy number variations (CNVs) involving proximal 1q21.1: 22 microdeletions and 20 reciprocal microduplications limited to proximal 1q21.1 and 13 microdeletions that include both the proximal and distal regions. Six individuals with proximal microdeletions have TAR syndrome. Three individuals with proximal microdeletions and two individuals with larger microdeletions of proximal and distal 1q21.1 have a 'partial' TAR phenotype. Furthermore, one subject with TAR syndrome has a smaller, atypical deletion, narrowing the critical deletion region for the syndrome. Otherwise, phenotypic features varied among individuals with these microdeletions and microduplications. The recurrent, proximal 1q21.1 microduplications are enriched in our population undergoing genetic testing compared with control populations. Therefore, CNVs in proximal 1q21.1 can be a contributing factor for the development of abnormal phenotypes in some carriers.

Topics: Adolescent; Child; Child, Preschool; Chromosome Deletion; Chromosome Duplication; Chromosomes, Human, Pair 1; Comparative Genomic Hybridization; Congenital Bone Marrow Failure Syndromes; DNA Copy Number Variations; Female; Gene Rearrangement; Genetic Testing; Humans; Infant; Infant, Newborn; Inheritance Patterns; Male; Pedigree; Phenotype; Radius; Thrombocytopenia; Upper Extremity Deformities, Congenital

PubMed: 22317977
DOI: 10.1038/ejhg.2012.6

Authors: João L Reis-Cunha, Samuel A Pimenta-Carvalho, Laila V Almeida...

Aneuploidy is widely observed in both unicellular and multicellular eukaryotes, usually associated with adaptation to stress conditions. Chromosomal duplication stability is a tradeoff between the fitness cost of having unbalanced gene copies and the potential fitness gained from increased dosage of specific advantageous genes. Trypanosomatids, a family of protozoans that include species that cause neglected tropical diseases, are a relevant group to study aneuploidies. Their life cycle has several stressors that could select for different patterns of chromosomal duplications and/or losses, and their nearly universal use of polycistronic transcription increases their reliance on gene expansion/contraction, as well as post-transcriptional control as mechanisms for gene expression regulation. By evaluating the data from 866 isolates covering seven trypanosomatid genera, we have revealed that aneuploidy tolerance is an ancestral characteristic of trypanosomatids but has a reduced occurrence in a specific monophyletic clade that has undergone large genomic reorganization and chromosomal fusions. We have also identified an ancient chromosomal duplication that was maintained across these parasite's speciation, named collectively as the trypanosomatid ancestral supernumerary chromosome (TASC). TASC has most genes in the same coding strand, is expressed as a disomic chromosome (even having four copies), and has increased potential for functional variation, but it purges highly deleterious mutations more efficiently than other chromosomes. The evidence of stringent control over gene expression in this chromosome suggests that these parasites have adapted to mitigate the fitness cost associated with this ancient chromosomal duplication.

Topics: Aneuploidy; Chromosome Duplication; Gene Expression Regulation; Genome, Protozoan; Evolution, Molecular; Trypanosomatina; Phylogeny

PubMed: 38604731
DOI: 10.1101/gr.278550.123

Authors: Yueli Wu, Linlin Zhang, Hong Lv...

The present study aimed to estimate the clinical performance of non-invasive prenatal testing (NIPT) based on high-throughput sequencing method for the detection of foetal chromosomal deletions and duplications. A total of 6348 pregnant women receiving NIPT using high-throughput sequencing method were included in our study. They all conceived naturally, without twins, triplets or multiple births. Individuals showing abnormalities in NIPT received invasive ultrasound-guided amniocentesis for chromosomal karyotype and microarray analysis at 18-24 weeks of pregnancy. Detection results of foetal chromosomal deletions and duplications were compared between high-throughput sequencing method and chromosomal karyotype and microarray analysis. Thirty-eight individuals were identified to show 51 chromosomal deletions/duplications via high-throughput sequencing method. In subsequent chromosomal karyotype and microarray analysis, 34 subchromosomal deletions/duplications were identified in 26 pregnant women. The observed deletions and duplications ranged from 1.05 to 17.98 Mb. Detection accuracy for these deletions and duplications was 66.7%. Twenty-one deletions and duplications were found to be correlated with the known abnormalities. NIPT based on high-throughput sequencing technique is able to identify foetal chromosomal deletions and duplications, but its sensitivity and specificity were not explored. Further progress should be made to reduce false-positive results.

Topics: Adult; Chromosome Deletion; Chromosome Duplication; Female; Fetus; High-Throughput Nucleotide Sequencing; Humans; Karyotyping; Noninvasive Prenatal Testing; Pregnancy; Sequence Analysis, DNA

PubMed: 32667743
DOI: 10.1111/jcmm.15593

Review

Authors: Ben J Mans, Jonathan Featherston, Minique H de Castro...

Ticks modulate their hosts' defense responses by secreting a biopharmacopiea of hundreds to thousands of proteins and bioactive chemicals into the feeding site (tick-host interface). These molecules and their functions evolved over millions of years as ticks adapted to blood-feeding, tick lineages diverged, and host-shifts occurred. The evolution of new proteins with new functions is mainly dependent on gene duplication events. Central questions around this are the rates of gene duplication, when they occurred and how new functions evolve after gene duplication. The current review investigates these questions in the light of tick biology and considers the possibilities of ancient genome duplication, lineage specific expansion events, and the role that positive selection played in the evolution of tick protein function. It contrasts current views in tick biology regarding adaptive evolution with the more general view that neutral evolution may account for the majority of biological innovations observed in ticks.

Topics: Adaptation, Physiological; Animals; Biological Evolution; Chromosome Duplication; Evolution, Molecular; Face; Feeding Behavior; Gene Duplication; Genetic Drift; Genetic Speciation; Host-Parasite Interactions; Multigene Family; Phylogeny; Salivary Glands; Ticks; Transcriptome

PubMed: 28993800
DOI: 10.3389/fcimb.2017.00413

Authors: Dharmagat Bhattarai, Daniel E McGinn, T Blaine Crowley...

PURPOSE

Duplication of chromosome 22q11.2 due to meiotic non-allelic homologous recombination results in a distinct syndrome, chromosome 22q11.2 duplication syndrome that has some overlapping phenotypic features with the corresponding 22q11.2 deletion syndrome. Literature on immunologic aspects of the duplication syndrome is limited. We conducted a retrospective study of 216 patients with this syndrome to better define the key features of the duplication syndrome.

METHODS

Single-center retrospective record review was performed. Data regarding demographics, clinical details, and immunological tests were compiled, extracted into a predetermined data collection form, and analyzed.

RESULTS

This cohort comprised 113 (52.3%) males and 103 (47.7%) females. The majority (54.6%) of mapped duplications were between low copy repeat regions A-D (LCR22A to -D). Though T cell subsets were relatively preserved, switched memory B cells, immunoglobulins, and specific antibodies were each found to be decreased in a subset of the cohort. One-fifth (17/79, 21.5%) of patients had at least 2 low immunoglobulin values, and panhypogammaglobulinemia was found in 11.7% (9/79) cases. Four children were on regular immunoglobulin replacement therapy. Asthma and eczema were the predominant atopic symptoms in our cohort.

CONCLUSION

Significant immunodeficiencies were observed in our cohort, particularly in B cells and antibodies. Our study expands the current clinical understanding and emphasizes the need of immunological studies and multidisciplinary approaches for these patients.

Topics: Male; Child; Chromosome Duplication; Syndrome; Humans; Chromosome Deletion; Abnormalities, Multiple; Retrospective Studies; DiGeorge Syndrome; Female; Chromosomes; Chromosomes, Human, Pair 22

PubMed: 36735193
DOI: 10.1007/s10875-023-01443-5

Authors: Panlai Shi, Conghui Wang, Yuting Zheng...

BACKGROUND

Distal 8p duplication is rare but clinically significant. Duplication syndrome results in variable phenotypes, such as developmental delay, intellectual disability, and malformation of the heart. We aimed to provide a better understanding of the phenotypes by studying duplication and its effects in a single family.

METHODS

In a family with a previously induced labor (second fetus) at 12 weeks gestation due to increased nuchal translucency (3.5 mm), copy number variation sequencing (CNV-seq) revealed a 16.22 Mb deletion of 8p23.3p22. For their subsequent pregnancy, the family requested a prenatal diagnosis as well as CNV-seq, karyotyping and FISH testing of all family members.

RESULTS

The first and third children were found to have a 16.22 Mb duplication of 8p23.3p22, containing the 8p23.1 duplication syndrome region. The duplication was inherited from their father, a carrier with a translocation of 8p22 and 22q13. We confirmed that the duplication site was located on chromosome 22q13 by combining the results of CNV-seq, karyotype and FISH. The first child is a 7.5-year-old boy. At one month old, he was diagnosed with a ventricular septal defect and treated surgically at age four. His growth and intelligence developed well, and he performed well in school. His primary issue is an inability to distinguish between the blade alveolars and retroflexes in speech. The third fetus had a normal ultrasound index from beginning until birth. The family elected to continue the pregnancy, and the baby was born healthy, providing us the opportunity to evaluate the effects of 8p23.3p22 duplication by comparison with the brother.

CONCLUSION

Our study makes a significant contribution to the literature because this relatively rare condition can have significant phenotypical consequences, and an understanding of the inheritance and variability of phenotypes caused by this mutation is essential to an increased understanding of the condition.

Topics: Adult; Child; Female; Humans; Infant; Infant, Newborn; Male; Pregnancy; Chromosome Duplication; Chromosomes, Human, Pair 8; Pedigree; Phenotype; Prenatal Diagnosis

PubMed: 33757501
DOI: 10.1186/s12920-021-00940-z