ABSTRACT
BACKGROUND: The MACF1 gene, found on chromosome 1p34.3, is vital for controlling cytoskeleton dynamics, cell movement, growth, and differentiation. It consists of 101 exons, spanning over 270 kb. The 16p13.11 microduplication syndrome results from the duplication of 16p13.11 chromosome copies and is associated with various neurodevelopmental and physiological abnormalities. Both MACF1 and 16p13.11 microduplication have significant impacts on neural development, potentially leading to nerve damage or neurological diseases. This study presents a unique case of a patient simultaneously experiencing a de novo MACF1 mutation and a hereditary 16p13.11 microduplication, which has not been reported previously. CASE PRESENTATION: In this report, we describe a Chinese preterm newborn girl exhibiting the typical characteristics of 16.13.11 microduplication syndrome. These features include developmental delay, respiratory issues, feeding problems, muscle weakness, excessive joint movement, and multiple congenital abnormalities. Through whole-exome sequencing, we identified a disease-causing mutation in the MACF1 gene (c.15266T > C / p. Met5089Thr). Additionally, after microarray analysis, we confirmed the presence of a 16p13.11 microduplication (chr16:14,916,289 - 16,315,688), which was inherited from the mother. CONCLUSIONS: The patient's clinical presentation, marked by muscle weakness and multiple birth defects, may be attributed to both the de novo MACF1 mutation and the 16p13.11 duplication, which could have further amplified her severe symptoms. Genetic testing for individuals with complex clinical manifestations can offer valuable insights for diagnosis and serve as a reference for genetic counseling for both patients and their families.
Subject(s)
Abnormalities, Multiple , Chromosomes, Human, Pair 16 , Muscle Hypotonia , Humans , Female , Infant, Newborn , Muscle Hypotonia/genetics , Chromosomes, Human, Pair 16/genetics , Abnormalities, Multiple/genetics , Infant, Premature , Chromosome Duplication , Mutation , Microfilament Proteins/geneticsABSTRACT
OBJECTIVE: To evaluate the technical accuracy, inheritance, and pathogenicity of small copy number variants (CNVs) detected by a targeted next-generation sequencing-based preimplantation genetic testing for aneuploidy (PGT-A) platform. DESIGN: Retrospective observational study performed between 2020 and 2022. SETTING: Clinic. PATIENT(S): A total of 12,157 patients who underwent clinical PGT-A performed by targeted next-generation sequencing for whole chromosome and large segmental aneuploidies. INTERVENTION(S): An incidental finding was reported when a CNV gain/loss of at least 3 consecutive amplicons appeared in at least 2 embryos from the same in vitro fertilization cycle. MAIN OUTCOME MEASURE(S): The primary outcome measures were the specificity, incidence, inheritance, and pathogenicity of small CNVs detected by the PGT-A platform. Accuracy of the PGT-A platform CNV calls was assessed via concordance with the CNV calls (size and genomic location) on chromosomal microarray of the gamete provider(s). Parental origin of the CNV and pathogenicity classifications were also reported. RESULT(S): An incidental finding that met reporting criteria was identified in 75 (0.62%; 95% confidence interval, 0.5%-0.8%) of 12,157 unique PGT-A patients. Chromosomal microarray follow-up was requested for all cases, and results were received for 1 or both members of 65 reproductive couples. In all cases, 1 of the gamete providers was confirmed to have the CNV identified in the embryos (100.0%, N = 65/65; 95% confidence interval, 94.5-100). The identified CNV was of maternal origin in 34 cases (52.3%) and of paternal origin in 31 cases (47.7%). A significant correlation was identified between PGT-A-predicted CNV sizes and chromosomal microarray detected sizes (r = 0.81) and genomic coordinates on parental deoxyribonucleic acid. Twenty-six (40%) of the CNVs were classified as benign/likely benign, 30 (46.2%) as a variant of uncertain significance, and 9 (13.8%) as pathogenic/likely pathogenic. CONCLUSION(S): Certain PGT-A platforms may enable the detection of inherited, small CNVs with extremely high specificity without prior knowledge of parental status. Most CNVs in this data set were confirmed to be benign/likely benign or a variant of uncertain significance. Pathogenic/likely pathogenic CNVs associated with a broad range of phenotypic features may also be detected, although a reliable negative predictive value for small CNVs with current PGT-A technologies is unknown because of the many technical challenges.
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BACKGROUND: Patients with 22q11.2 microduplication syndrome exhibit a high degree of phenotypic heterogeneity and incomplete penetrance, making prenatal diagnosis challenging due to phenotypic variability. This report aims to raise awareness among prenatal diagnostic practitioners regarding the variant's complexity, providing a basis for prenatal genetic counseling. METHODS: Family and clinical data of 31 fetuses with 22q11.2 microduplications confirmed by chromosomal microarray between June 2017 and June 2023 were considered. RESULTS: Primary prenatal ultrasound features of affected fetuses include variable cardiac and cardiovascular anomalies, increased nuchal translucency (≥3 mm), renal abnormalities, and polyhydramnios. More than half of fetuses considered showed no intrauterine manifestations; therefore, prenatal diagnostic indicators were primarily advanced maternal age or high-risk Down syndrome screening. Most fetuses had microduplications in proximal or central 22q11.2 regions, with only three cases with distal microduplications. Among parents of fetuses considered, 87% (27/31) continued the pregnancy. During follow-up, 19 cases remained clinically asymptomatic. CONCLUSION: Nonspecific 22q11.2 microduplication features in fetuses and its mild postnatal disease presentation highlight the need to cautiously approach prenatal diagnosis and pregnancy decision-making. Increased clinical efforts should be made regarding providing parents with specialized genetic counseling, long-term follow-up, and fetal risk information.
Subject(s)
DiGeorge Syndrome , Female , Humans , Pregnancy , Abnormalities, Multiple , China , Chromosome Duplication , Chromosomes, Human, Pair 22/genetics , DiGeorge Syndrome/genetics , DiGeorge Syndrome/diagnosis , East Asian People , Fetus/abnormalities , Genetic Testing , Prenatal Diagnosis , Ultrasonography, PrenatalABSTRACT
Duplication is a foundation of molecular evolution and a driver of genomic and complex diseases. Here, we develop a genome editing tool named Amplification Editing (AE) that enables programmable DNA duplication with precision at chromosomal scale. AE can duplicate human genomes ranging from 20 bp to 100 Mb, a size comparable to human chromosomes. AE exhibits activity across various cell types, encompassing diploid, haploid, and primary cells. AE exhibited up to 73.0% efficiency for 1 Mb and 3.4% for 100 Mb duplications, respectively. Whole-genome sequencing and deep sequencing of the junctions of edited sequences confirm the precision of duplication. AE can create chromosomal microduplications within disease-relevant regions in embryonic stem cells, indicating its potential for generating cellular and animal models. AE is a precise and efficient tool for chromosomal engineering and DNA duplication, broadening the landscape of precision genome editing from an individual genetic locus to the chromosomal scale.
Subject(s)
Gene Duplication , Gene Editing , Genome, Human , Humans , Gene Editing/methods , CRISPR-Cas Systems/genetics , DNA/genetics , Animals , Embryonic Stem Cells/metabolism , Chromosomes, Human/geneticsABSTRACT
Given the crucial role of the personalized management and treatment of hearing loss (HL), etiological investigations are performed early on, and genetic analysis significantly contributes to the determination of most syndromic and nonsyndromic HL cases. Knowing hundreds of syndromic associations with HL, little comprehensive data about HL in genomic disorders due to microdeletion or microduplications of contiguous genes is available. Together with the description of a new patient with a novel 3.7 Mb deletion of the Xq21 critical locus, we propose an unreported literature review about clinical findings in patients and their family members with Xq21 deletion syndrome. We finally propose a comprehensive review of HL in contiguous gene syndromes in order to confirm the role of cytogenomic microarray analysis to investigate the etiology of unexplained HL.
Subject(s)
Chromosome Deletion , Chromosomes, Human, X , Hearing Loss , Humans , Chromosomes, Human, X/genetics , Hearing Loss/genetics , Male , Syndrome , Female , PedigreeABSTRACT
BACKGROUND: Chromosomal microarray analysis is an essential tool for copy number variants detection in patients with unexplained developmental delay/intellectual disability, autism spectrum disorders, and multiple congenital anomalies. The study aims to determine the clinical significance of chromosomal microarray analysis in this patient group. Another crucial aspect is the evaluation of copy number variants detected in terms of the diagnosis of patients. METHODS AND RESULTS: A Chromosomal microarray analysis was was conducted on a total of 1227 patients and phenotype-associated etiological diagnosis was established in 135 patients. Phenotype-associated copy number variants were detected in 11% of patients. Among these, 77 patients 77 (57%, 77/135) were diagnosed with well-recognized genetic syndromes and phenotype-associated copy number variants were found in 58 patients (42.9%, 58/135). The study was designed to collect data of patients in Kocaeli Derince Training and Research Hospital retrospectively. In our study, we examined 135 cases with clinically significant copy number variability among all patients. CONCLUSIONS: In this study, chromosomal microarray analysis revealed pathogenic de novo copy number variants with new clinical features. Chromosomal microarray analysis in the Turkish population has been reported in the largest patient cohort to date.
Subject(s)
Abnormalities, Multiple , Autism Spectrum Disorder , DNA Copy Number Variations , Developmental Disabilities , Humans , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/diagnosis , Turkey/epidemiology , DNA Copy Number Variations/genetics , Female , Male , Child , Child, Preschool , Developmental Disabilities/genetics , Developmental Disabilities/diagnosis , Abnormalities, Multiple/genetics , Abnormalities, Multiple/diagnosis , Adolescent , Phenotype , Infant , Intellectual Disability/genetics , Intellectual Disability/diagnosis , Chromosome Aberrations , Microarray Analysis/methods , Retrospective Studies , AdultABSTRACT
BACKGROUND: Silver-Russel syndrome (SRS) is a congenital disorder which is mainly characterized by intrauterine and postnatal growth retardation, relative macrocephaly, and characteristic (facial) dysmorphisms. The majority of patients shows a hypomethylation of the imprinting center region 1 (IC1) in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat), but in addition a broad spectrum of copy number variations (CNVs) and monogenetic variants (SNVs) has been reported in this cohort. These heterogeneous findings reflect the clinical overlap of SRS with other congenital disorders, but some of the CNVs are recurrent and have therefore been suggested as SRS-associated loci. However, this molecular heterogeneity makes the decision on the diagnostic workup of patients with SRS features challenging. CASE PRESENTATION: A girl with clinical features of SRS but negatively tested for the IC1 hypomethylation and upd(7)mat was analyzed by whole genome sequencing in order to address both CNVs and SNVs in the same run. We identified a 11p13 microduplication affecting a region overlapping with a variant reported in a previously published patient with clinical features of Silver-Russel syndrome. CONCLUSIONS: The identification of a 11p13 microduplication in a patient with SRS features confirms the considerable contribution of CNVs to SRS-related phenotypes, and it strengthens the evidence for a 11p13 microduplication syndrome as a differential diagnosis SRS. Furthermore, we could confirm that WGS is a valuable diagnostic tool in patients with SRS and related disorders, as it allows CNVs and SNV detection in the same run, thereby avoiding a time-consuming diagnostic testing process.
ABSTRACT
We present a series of microdeletion and microduplication syndromes (MMSs) observed in our clinical practice over a three-year period from 2020 to 2023. Microdeletion and microduplication syndromes, characterized by chromosomal deletions or duplications of less than five megabases, pose challenges in terms of diagnosis, especially prenatal and clinical management. Clinically, MMSs encompass a broad spectrum of manifestations, ranging from intellectual disability and developmental delays to congenital anomalies, facial dysmorphisms, and neurobehavioral abnormalities. Notable examples include well-characterized syndromes such as DiGeorge syndrome (22q11.2 deletion), Prader-Willi syndrome (15q11-q13 deletion), and Williams syndrome (7q11 deletion). Our study focuses on the genetic foundations and prenatal ultrasound findings of these syndromes, with an emphasis on cases associated with intellectual disability. Using SNP array technology, we delve into the evolving landscape of diagnostic methods, providing a nuanced understanding of copy number variations (CNVs) and their implications. Prenatal diagnosis allows for the early detection of MMSs, enabling parents and healthcare providers to make informed decisions about the pregnancy and plan for appropriate medical care and interventions. Beyond theoretical considerations, our article bridges the gap between research and practical application by offering insights derived from clinical cases. Through the presentation of specific cases, we aim to contribute valuable data to the broader discourse on MMSs, fostering knowledge exchange and enhancing the medical community's awareness of these complex genetic conditions.
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BACKGROUND: Potocki-Lupski syndrome (PTLS, OMIM # 610883) is a rare genetic developmental disorder resulting from a partial heterozygous microduplication at chromosome 17p11.2. The condition is characterized by a wide variability of clinical expression, which can make its clinical and molecular diagnosis challenging. CASE PRESENTATION: We report here a family (mother and her two children) diagnosed with PTLS. When examining children, neurological and psychological (neuropsychiatric) manifestations (speech delay, mild mental retardation), motor disorders, craniofacial dysmorphism (microcephaly, dolichocephaly, triangular face, wide bulging forehead, long chin, antimongoloid slant, "elfin" ears) were revealed. The suspected clinical diagnosis was confirmed by MLPA and CMA molecular genetic testing which revealed the presence of a segmental aneusomy; microduplication in the 17p11.2 region. CONCLUSIONS: Children with PTLS can have a clinically recognizable and specific phenotype: craniofacial dysmorphism, motor and neurological manifestations, which may implicate a possible genetic disease to the attending physician. Moreover, each child with this syndrome is unique and may have a different clinical picture. The management of such patients requires a multidisciplinary team approach, including medical genetic counseling.
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OBJECTIVE: We present incidental detection of familial 8p23.2 microduplication encompassing CSMD1 associated with mosaic 46,XY,t(7;8)(q31.2;p23.1)/46,XY at amniocentesis in a pregnancy with no apparent phenotypic abnormality and a favorable outcome. CASE REPORT: A 38-year-old, gravida 2, para 1, phenotypically normal woman underwent amniocentesis at 19 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY,t(7;8)(q31.2;p23.1)[2]/46,XY[20]. The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from cultured amniocytes and parental bloods revealed the result of a 2.178-Mb 8p23.2 microduplication encompassing CSMD1, or arr 8p23.2 (3,070,237-5,248,586) × 3.0 [GRCh37 (hg19)] in the fetus and the mother. The father did not have such a microduplicaiton. Prenatal ultrasound findings were unremarkable. At 38 weeks of gestation, a 2880-g phenotypically normal male baby was delivered. All the cord blood, umbilical cord and placenta had the karyotype of 46.XY. When follow-up at age six months, the neonate was normal in phenotype and development. CONCLUSION: Mosaicism for a balanced reciprocal translocation with a euploid cell line can be a transient and benign condition. Familial 8p23.2 microduplication encompassing CSMD1 can be associated with a favorable outcome.
Subject(s)
Amniocentesis , Mosaicism , Pregnancy , Infant, Newborn , Female , Male , Humans , Infant , Adult , Comparative Genomic Hybridization , Karyotyping , Karyotype , Trisomy , Membrane Proteins , Tumor Suppressor ProteinsABSTRACT
BACKGROUND: Limited research has been conducted regarding the elucidation of genotype-phenotype correlations within the 20q13.33 region. The genotype-phenotype association of 20q13.33 microdeletion remains inadequately understood. In the present study, two novel cases of 20q13.33 microdeletion were introduced, with the objective of enhancing understanding of the genotype-phenotype relationship. METHODS: Two unrelated patients with various abnormal clinical phenotypes from Fujian province Southeast China were enrolled in the present study. Karyotype analysis and chromosomal microarray analysis (CMA) were performed to investigate chromosomal abnormalities and copy number variants. RESULTS: The results of high-resolution G-banding karyotype analysis elicited a 46,XY,der(20)add(20)(q13.3) in Patient 1. This patient exhibited various clinical manifestations, such as global developmental delay, intellectual disability, seizures, and other congenital diseases. Subsequently, a 1.0-Mb deletion was identified in the 20q13.33 region alongside a 5.2-Mb duplication in the 14q32.31q32.33 region. In Patient 2, CMA results revealed a 1.8-Mb deletion in the 20q13.33 region with a 4.8-Mb duplication of 17q25.3. The patient exhibited additional abnormal clinical features, including micropenis, congenital heart disease, and a distinctive crying pattern characterized by a crooked mouth. CONCLUSION: In the present study, for the first time, an investigation was conducted into two novel cases of 20q13.33 microdeletion with microduplications in the 17q25.3 and 14q32.31q32.33 regions in the Chinese population. The presence of micropenis may be attributed to the 20q13.33 microdeletion, potentially expanding the phenotypic spectrum associated with this deletion.
Subject(s)
Chromosome Structures , Genital Diseases, Male , Intellectual Disability , Penis/abnormalities , Child , Humans , Intellectual Disability/genetics , Karyotyping , KaryotypeABSTRACT
PURPOSE: The preimplantation genetic testing for aneuploidy (PGT-A) platform is not currently available for small copy-number variants (CNVs), especially those < 1 Mb. Through strategies used in PGT for monogenic disease (PGT-M), this study intended to perform PGT for families with small pathogenic CNVs. METHODS: Couples who carried small pathogenic CNVs and underwent PGT at the Reproductive and Genetic Hospital of CITIC-Xiangya (Hunan, China) between November 2019 and April 2023 were included in this study. Haplotype analysis was performed through two platforms (targeted sequencing and whole-genome arrays) to identify the unaffected embryos, which were subjected to transplantation. Prenatal diagnosis using amniotic fluid was performed during 18-20 weeks of pregnancy. RESULTS: PGT was successfully performed for 20 small CNVs (15 microdeletions and 5 microduplications) in 20 families. These CNVs distributed on chromosomes 1, 2, 6, 7, 13, 15, 16, and X with sizes ranging from 57 to 2120 kb. Three haplotyping-based PGT-M strategies were applied. A total of 89 embryos were identified in 25 PGT cycles for the 20 families. The diagnostic yield was 98.9% (88/89). Nineteen transfers were performed for 17 women, resulting in a 78.9% (15/19) clinical pregnancy rate after each transplantation. Of the nine women who had healthy babies, eight accepted prenatal diagnosis and the results showed no related pathogenic CNVs. CONCLUSION: Our results show that the extended haplotyping-based PGT-M strategy application for small pathogenic CNVs compensated for the insufficient resolution of PGT-A. These three PGT-M strategies could be applied to couples with small pathogenic CNVs.
Subject(s)
Abortion, Spontaneous , Preimplantation Diagnosis , Pregnancy , Humans , Female , Preimplantation Diagnosis/methods , Genetic Testing/methods , Pregnancy Rate , Abortion, Spontaneous/genetics , Live Birth , AneuploidyABSTRACT
OBJECTIVE: The etiology of congenital talipes equinovarus (CTEV) is unknown, and the relationship between chromosome microdeletion/microduplication and fetal CTEV is rarely reported. In this study, we retrospectively analyzed fetal CTEV to explore the relationship among the CTEV phenotype, chromosome microdeletion/microduplication, and obstetric outcomes. METHODS: Chromosome karyotype analysis and single nucleotide polymorphism (SNP) array were performed for the 68 fetuses with CTEV. RESULTS: An SNP array was performed for 68 fetuses with CTEV; pathogenic copy number variations (CNVs) were detected in eight cases (11.8%, 8/68). In addition to one case consistent with karyotype analysis, the SNP array revealed seven additional pathogenic CNVs, including three with 22q11.21 microdeletions, two with 17p12p11.2 microduplications, one with 15q11.2 microdeletions, and one with 7q11.23 microduplications. Of the seven cases carrying pathogenic CNVs, three were tested for family genetics; of these, one was de novo, and two were inherited from either the father or mother. In total, 68 fetuses with CTEV were initially identified, of which 66 cases successfully followed-up. Of these, 9 were terminated, 2 died in utero, and 55 were live births. In 9 cases, no clinical manifestations of CTEV were found at birth; the false-positive rate of prenatal ultrasound CTEVdiagnosis was thus 13.6% (9/66). CONCLUSION: CTEV was associated with chromosome microdeletion/microduplication, the most common of which was 22q11.21 microdeletion, followed by 17p12p11.2 microduplication. Thus, further genomic detection is recommended for fetuses with CTEV showing no abnormalities on conventional karyotype analysis.
Subject(s)
Clubfoot , Pregnancy , Infant, Newborn , Female , Humans , Clubfoot/genetics , Retrospective Studies , DNA Copy Number Variations , Follow-Up Studies , Fetus , Genomics , Prenatal DiagnosisABSTRACT
Objective:To analyze the prenatal characteristics and pregnancy outcomes of fetuses with 17q12 microdeletion or microduplication.Methods:From January 2018 to December 2022, 14 fetuses diagnosed with 17q12 microdeletion and three with 17q12 microduplication by chromosomal microarray analysis folloning invasive prenatal diagnostic techniques at Nanjing Maternity and Child Health Care Hospital were retrospectively enrolled in this study. Relevant articles up to February 1, 2023, were retrieved from PubMed, Embase, China National Knowledge Infrastructure, Wanfang database, and Yiigle with the terms "17q12 microdeletion", "17q12 microduplication", "prenatal diagnosis", and "pregnancy outcome". Eighty-four 17q12 microdeletion cases and fourteen 17q12 microduplication cases were retrieved. Prenatal ultrasound features and pregnancy outcomes of those fetuses were analyzed and summarized.Results:In this study, ninety-eight 17q12 microdeletion cases and seventeen 17q12 microduplication cases were analyzed. (1) 17q12 microdeletion: The prenatal ultrasound showed all the 17q12 microdeletion cases had renal abnormalities (100.0%, 98/98), and renal hyperechogenicity was detected in 81.6% (80/98) of them; pedigree analysis suggested that 74.2% (49/66) mutations were de novo; 64.1% (41/64) of pregnant women chose to terminate the pregnancy and 35.9%(23/64) chose to continue pregnancy; eight out of 12 live births who were followed up had different degrees of abnormalities and four were normal during the follow-up period. (2) 17q12 microduplication: Among the 17 fetuses, 10 had upper gastrointestinal obstruction; pedigree analysis suggested that four were de novo mutations (4/13); nine out of 14 pregnant women with reported pregnancy outcomes chose to terminate the pregnancy, and five continued the pregnancy to delivery; follow up of the live births found that four neonates were normal and one had a good prognosis after surgery. Conclusions:Fetuses with 17q12 microdeletion often show renal hyperechogenicity in ultrasound images, and most mutations were de novo with poor prognosis. 17q12 microduplication in fetuses is often characterized by upper gastrointestinal obstruction, and most inherited from their parents.
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Autism spectrum disorder (ASD) is characterized by multifactorial etiology and high heritability but can be challenging to be diagnosed, especially in cases presenting subthreshold symptoms with no cognitive or language impairment, which may not be identified until adulthood but may occur in family members of subjects with ASD. This study explores the possible correlation between a genomic imbalance and clinical phenotypes in a family case of a proband with ASD, with subjects presenting full-blown or subthreshold ASD and/or mood disorders. Clinical assessments were carried out by means of the Structured Clinical Interview for DSM-5 (SCID-5) disorders, Autism Spectrum Quotient (AQ), Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule Module 2 (ADOS-2), and Adult Autism Subthreshold Spectrum (AdAS Spectrum). The genetic evaluation included array comparative genomic hybridization (array-CGH). The proband was diagnosed with ASD and bipolar disorder type I (BD-I), her twin brothers with ASD and intellectual disability (ID), and her father and sister with BD type II (BD-II) and autism traits. The proband, her father, twin brothers, and older sister showed a microduplication of 350 kb in 20q11.21. In contrast, the proband's mother did not present the microduplication or any mental disorder. This study reports a microduplication that segregates with family members affected by ASD or autistic traits comorbid in some cases with bipolar disorder, and that has never been reported in healthy subjects. Among the genes harbored in this region, the TM9SF4 gene has been recently implicated in risk for ASD.
ABSTRACT
Chromosomal submicroscopic imbalances represent well-known causes of neurodevelopmental disorders. In some cases, these can cause specific autosomal dominant syndromes, with high-to-complete penetrance and de novo occurrence of the variant. In other cases, they result in non-syndromic neurodevelopmental disorders, often acting as moderate-penetrance risk factors, possibly inherited from unaffected parents. We describe a three-generation family with non-syndromic neuropsychiatric features segregating with a novel 19q13.32q13.33 microduplication. The propositus was a 28-month-old male ascertained for psychomotor delay, with no dysmorphic features or malformations. His mother had Attention-Deficit/Hyperactivity Disorder and a learning disability. The maternal uncle had an intellectual disability. Chromosomal microarray analysis identified a 969 kb 19q13.32q13.33 microduplication in the proband. The variant segregated in the mother, the uncle, and the maternal grandmother of the proband, who also presented neuropsychiatric disorders. Fragile-X Syndrome testing was negative. Exome Sequencing did not identify Pathogenic/Likely Pathogenic variants. Imbalances involving 19q13.32 and 19q13.33 are associated with neurodevelopmental delay. A review of the reported microduplications allowed to propose BICRA (MIM *605690) and KPTN (MIM *615620) as candidates for the neurodevelopmental delay susceptibility in 19q13.32q13.33 copy number gains. The peculiarities of this case are the small extension of the duplication, the three-generation segregation, and the full penetrance of the phenotype.
Subject(s)
Intellectual Disability , Neurodevelopmental Disorders , Male , Humans , Child, Preschool , Phenotype , Transcription Factors/genetics , Neurodevelopmental Disorders/genetics , Intellectual Disability/genetics , Intellectual Disability/pathology , Family , Microfilament Proteins/geneticsABSTRACT
Large-scale genomic structural variations can have significant clinical implications, depending on the specific altered genomic region. Briefly, 2q37 microdeletion syndrome is a prevalent subtelomeric deletion disorder characterized by variable-sized deletions. Affected patients exhibit a wide range of clinical manifestations, including short stature, facial dysmorphism, and features of autism spectrum disorder, among others. Conversely, isolated duplications of proximal chromosome 2q are rare and lack a distinct phenotype. In this report, we provide an extensive molecular analysis of a 15-day-old newborn referred for syndromic features. Our analysis reveals an 8.5 Mb microdeletion at 2q37.1, which extends to the telomere, in conjunction with an 8.6 Mb interstitial microduplication at 2q34q36.1. Our findings underscore the prominence of 2q37 terminal deletions as commonly reported genomic anomalies. We compare our patient's phenotype with previously reported cases in the literature to contribute to a more refined classification of 2q37 microdeletion syndrome and assess the potential impact of 2q34q36.1 microduplication. We also investigate multiple hypotheses to clarify the genetic mechanisms responsible for the observed genomic rearrangement.
Subject(s)
Autism Spectrum Disorder , Intellectual Disability , Infant, Newborn , Humans , Chromosome Deletion , Intellectual Disability/genetics , Autism Spectrum Disorder/genetics , Chromosome Structures , TelomereABSTRACT
This study reports the first case of a patient with chromosomal 2p16.1p15 microduplication syndrome complicated by pulmonary arterial hypertension (PAH). A female infant was admitted to the hospital suffering from dyskinesia and developmental delay, and conventional echocardiography revealed an atrial septal defect (ASD), which was not taken seriously or treated at that time. Two years later, preoperative right heart catheterization for ASD closure revealed a mean pulmonary artery pressure (mPAP) of 45 mmHg. The mPAP was reduced, and the condition was stabilized after drug therapy. A genomic copy number duplication (3×) of at least 2.58â Mb in the 2p16.1p15 region on the paternal chromosome was revealed. Multiple Online Mendelian Inheritance in Man (OMIM) genes are involved in this genomic region, such as BCL11A, EHBP1, FAM161A, PEX13, and REL. EHBP1 promotes a molecular phenotypic transformation of pulmonary vascular endothelial cells and is thought to be involved in the rapidly developing PAH of this infant. Collectively, our findings contribute to the knowledge of the genes involved and the clinical manifestations of the 2p16.1p15 microduplication syndrome. Moreover, clinicians should be alert to the possibility of PAH and take early drug intervention when facing patients with 2p16.1p15 microduplications.
ABSTRACT
OBJECTIVE: We present genetic counseling of a prenatally detected familial 18.79-kb Xp21.1 microduplication encompassing exon 13 of DMD in a pregnancy with no apparent phenotypic abnormalities in the male carriers in the family. CASE REPORT: A 35-year-old, gravida 2, para 0, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY. Simultaneous aCGH analysis on the DNA extracted from uncultured amniocytes revealed an 18.79-kb Xp21.1 microduplication, or arr Xp21.1 (32,608,400-32,627,193) × 2.0 [GRCh37 (hg19)] encompassing only exon 13 of the gene of DMD (31,137,345-33,357,706) [GRCh37 (hg19)]. Multiplex ligation-dependent probe amplification (MLPA) analysis of the family showed that the mother and her 32-year-old brother carried the same duplication but without apparent phenotypic abnormalities and no features of DMD. Prenatal ultrasound was normal. She was referred for genetic counseling at 24 weeks of gestation, and continuing pregnancy was advised. At 38 weeks of gestation, a 3530-g phenotypically normal male baby was delivered. aCGH analysis of the umbilical cord confirmed the result of arr Xp21.1 (32,608,400-32,627,193) × 2.0 [GRCh37 (hg19)] encompassing only exon 13 of the gene of DMD (31,137,345-33,357,706) [GRCh37 (hg19)]. CONCLUSION: Xp21.1 microduplication encompassing exon 13 of the DMD gene can be a benign genetic variant.
Subject(s)
Amniocentesis , Genetic Counseling , Humans , Infant , Female , Pregnancy , Male , Adult , Exons/genetics , Gravidity , KaryotypeABSTRACT
Se presenta un niño de 6 años con antecedente de retraso del lenguaje que llevó a sus padres a realizar múltiples consultas. En un primer momento, su cuadro fue interpretado como parte de un retraso global del desarrollo. Posteriormente, el paciente presentó convulsiones y episodios de descompensación metabólica, comenzando desde entonces su seguimiento por los Servicios de neurología, genética y metabolismo. Finalmente, tras varios estudios complementarios, por medio de un exoma trío se arribó al diagnóstico de síndrome de microduplicación del cromosoma 7q11.23, lo que justifica tanto el retraso global de desarrollo del paciente como su clínica neurológica. (AU)
A six-year-old boy presents with a history of language delay that led his parents to make multiple consultations. At first, we interpreted his condition as part of a global developmental delay. Subsequently, the patient presented seizures and episodes of metabolic decompensation, and since then, he had to be followed up by neurology, genetics, and metabolism services. Finally, after several complementary studies, following a trio exome analysis, we diagnosed chromosome 7q11.23 microduplication syndrome, which explains his global developmental delay and neurological symptoms. (AU)