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Fertility and Sterility Feb 2018Chromosomal microarray analysis (CMA) is performed either by array comparative genomic hybridization or by using a single nucleotide polymorphism array. In the prenatal... (Review)
Review
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 -
Genetics in Medicine : Official Journal... Apr 2016To 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...
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 -
Neurogenetics Aug 2019Both copy number losses and gains occur within subtelomeric 9q34 region without common breakpoints. The microdeletions cause Kleefstra syndrome (KS), whose responsible...
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 -
Clinical Dysmorphology Jul 2020The clinical phenotype of 1q21.1 microdeletion syndrome is highly heterogeneous. It is characterized by dysmorphic facial features, microcephaly, and developmental... (Review)
Review
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 -
European Journal of Human Genetics :... Jul 2012Chromosomal band 1q21.1 can be divided into two distinct regions, proximal and distal, based on segmental duplications that mediate recurrent rearrangements....
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 -
Human Molecular Genetics Oct 2020Deletions spanning the STS (steroid sulfatase) gene at Xp22.31 are associated with X-linked ichthyosis, corneal opacities, testicular maldescent, cardiac arrhythmia, and...
Deletions spanning the STS (steroid sulfatase) gene at Xp22.31 are associated with X-linked ichthyosis, corneal opacities, testicular maldescent, cardiac arrhythmia, and higher rates of developmental and mood disorders/traits, possibly related to the smaller volume of some basal ganglia structures. The consequences of duplication of the same genomic region have not been systematically assessed in large or adult samples, although evidence from case reports/series has indicated high rates of developmental phenotypes. We compared multiple measures of physical and mental health, cognition and neuroanatomy in male (n = 414) and female (n = 938) carriers of 0.8-2.5 Mb duplications spanning STS, and non-carrier male (n = 192, 826) and female (n = 227, 235) controls from the UK Biobank (recruited aged 40-69 from the UK general population). Clinical and self-reported diagnoses indicated a higher prevalence of inguinal hernia and mania/bipolar disorder respectively in male duplication carriers, and a higher prevalence of gastro-oesophageal reflux disease and blistering/desquamating skin disorder respectively in female duplication carriers; duplication carriers also exhibited reductions in several depression-related measures, and greater happiness. Cognitive function and academic achievement did not differ between comparison groups. Neuroanatomical analysis suggested greater lateral ventricle and putamen volume in duplication carriers. In conclusion, Xp22.31 duplications appear largely benign, but could slightly increase the likelihood of specific phenotypes (although results were only nominally-significant). In contrast to deletions, duplications might protect against depressive symptoms, possibly via higher STS expression/activity (resulting in elevated endogenous free steroid levels), and through contributing towards an enlarged putamen volume. These results should enable better genetic counselling of individuals with Xp22.31 microduplications.
Topics: Aged; Biological Specimen Banks; Chromosome Duplication; Chromosomes, Human, X; Cognition; Comparative Genomic Hybridization; Female; Genetic Diseases, X-Linked; Heterozygote; Humans; Ichthyosis, X-Linked; Male; Mental Health; Middle Aged; Neuroanatomy; Steryl-Sulfatase; United Kingdom
PubMed: 32766777
DOI: 10.1093/hmg/ddaa174 -
Molecular Genetics & Genomic Medicine Mar 2021Recent studies suggest that duplication of the 9p24.3 chromosomal locus, which includes the DOCK8 and KANK1 genes, is associated with autism spectrum disorders (ASD),...
BACKGROUND
Recent studies suggest that duplication of the 9p24.3 chromosomal locus, which includes the DOCK8 and KANK1 genes, is associated with autism spectrum disorders (ASD), intellectual disability/developmental delay (ID/DD), learning problems, language disorders, hyperactivity, and epilepsy. Correlation between this duplication and the carrier phenotype needs further discussion.
METHODS
In this study, three unrelated patients with ID/DD and ASD underwent SNP aCGH and MLPA testing. Similarities in the phenotypes of patients with 9p24.3, 15q11.2, and 16p11.2 duplications were also observed.
RESULTS
All patients with ID/DD and ASD carried the 9p24.3 duplication and showed intragenic duplication of DOCK8. Additionally, two patients had ADHD, one was hearing impaired and obese, and one had macrocephaly. Inheritance of the 9p24.3 duplication was confirmed in one patient and his sibling. In one patient KANK1 was duplicated along with DOCK8. Carriers of 9p24.3, 15q11.2, and 16p11.2 duplications showed several phenotypic similarities, with ID/DD more strongly associated with duplication of 9p24.3 than of 15q11.2 and 16p11.2.
CONCLUSION
We concluded that 9p24.3 is a likely cause of ASD and ID/DD, especially in cases of DOCK8 intragenic duplication. DOCK8 is a likely causative gene, and KANK1 aberrations a modulator, of the clinical phenotype observed. Other modulators were not excluded.
Topics: Adaptor Proteins, Signal Transducing; Child; Child, Preschool; Chromosome Disorders; Chromosome Duplication; Chromosomes, Human, Pair 9; Cytoskeletal Proteins; Developmental Disabilities; Female; Guanine Nucleotide Exchange Factors; Humans; Male; Phenotype
PubMed: 33455084
DOI: 10.1002/mgg3.1592 -
Frontiers in Cellular and Infection... 2017Ticks modulate their hosts' defense responses by secreting a biopharmacopiea of hundreds to thousands of proteins and bioactive chemicals into the feeding site... (Review)
Review
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 -
Neurology India Jan 2024Chromosomal deletion and duplication syndromes can lead to intellectual disability, autism, microcephaly, and poor growth. Usually manifestations of duplication...
Chromosomal deletion and duplication syndromes can lead to intellectual disability, autism, microcephaly, and poor growth. Usually manifestations of duplication syndromes are milder than that of the deletion syndromes. With the availability of tests for analysis of copy number variants, it is possible to identify the deletion and duplication syndromes with greater ease. We report 32 cases of chromosomal duplication syndromes, identified in children presenting with developmental delay, intellectual disability, or microcephaly and/or additional features, at a tertiary care center on karyotyping or microarray analysis. Seven were isolated duplications, and one child had an additional smaller pathogenic deletion. Thus, duplication syndromes can have milder presentations with spectrum of dysmorphism, behavioral problems, and intellectual disability, but it is possible to diagnose easily with latest emerging high-throughput technologies.
Topics: Child; Humans; Chromosome Duplication; Microcephaly; Intellectual Disability; Research; Chromosome Deletion; Syndrome
PubMed: 38443013
DOI: 10.4103/ni.ni_400_21 -
BMC Medical Genomics Mar 2021Distal 8p duplication is rare but clinically significant. Duplication syndrome results in variable phenotypes, such as developmental delay, intellectual disability, and...
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: Chromosomes, Human, Pair 8; DNA Copy Number Variations; Female; Humans; Infant; Karyotyping; Male; Phenotype; Pregnancy; Trisomy
PubMed: 33757501
DOI: 10.1186/s12920-021-00940-z