Motor difficulties in 16p11.2 copy number variation.

The rare genetic variants 16p11.2 duplication and 16p11.2 deletion have opposing effects on brain structure and function, yet are associated with broadly similar clinical phenotypes that include autism, intellectual impairment, psychiatric illness, and motor difficulties. In recent years, studies have identified subtle distinctions between the phenotypic effects of 16p11.2 duplication and 16p11.2 deletion with respect to patterns of autism, intellectual impairment, and psychiatric illness. However, although divergent phenotypic findings in some motor domains have been reported, no study has yet made a comprehensive comparison of motor difficulties between 16p11.2 deletion and 16p11.2 duplication carriers to elucidate points of convergence and divergence. We sought to make such a comparison in a group of 133 16p11.2 deletion carriers, 122 duplication carriers, and 388 familial controls, hypothesizing that motor impairment would overall be greater in deletion than duplication carriers. In a series of regression models, we found that 16p11.2 deletion status tended to predict greater impairment along indices of gross motor function, but less impairment along indices of fine motor function. These findings point to a potential pattern of performance difficulties that could be investigated in future studies. Elucidating motor differences between 16p11.2 duplication and 16p11.2 deletion carriers may help in understanding the complex effect of 16p11.2 copy number variation and other rare genetic causes of autism.

Chromosomal Duplication Syndromes: A Case Series.

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.

Unilateral Retinopathy in a Preterm Infant With 4q Duplication: Description and Management.

A 33-5/7, 1570 g dichorionic diamniotic twin presented with cryptorchidism, failed hearing examination (both ears), poor feeding, profound hypoglycemia, coagulopathy, conjugated hyper-bilirubinemia, hydronephrosis, and hypotension. Microarray sent with results of whole genome SNP microgray analysis detected an interstitial duplication of the chromosomal segment 4q35 1q35.2. On this basis, telemedicine screening was performed to evaluate for ocular abnormalities in association with abnormal gene testing. Unilateral advanced retinopathy was noted affecting the right eye, with mature vascularization in the left eye. This infant was managed in concordance with retinopathy of prematurity guidelines, despite not making screening criteria. Off-label intravitreal bevacizumab injection (0.625 mg in 0.025 mL) resulted in full vascular maturation assessed by fluorescein angiography 6 months later. This represents the first description and management of retinopathy in 4q duplication syndrome. [Ophthalmic Surg Lasers Imaging Retina 2024;55:228-230.].

Refining the 9q34.3 microduplication syndrome reveals mild neurodevelopmental features associated with a distinct global DNA methylation profile.

Precise regulation of gene expression is important for correct neurodevelopment. 9q34.3 deletions affecting the EHMT1 gene result in a syndromic neurodevelopmental disorder named Kleefstra syndrome. In contrast, duplications of the 9q34.3 locus encompassing EHMT1 have been suggested to cause developmental disorders, but only limited information has been available. We have identified 15 individuals from 10 unrelated families, with 9q34.3 duplications <1.5 Mb in size, encompassing EHMT1 entirely. Clinical features included mild developmental delay, mild intellectual disability or learning problems, autism spectrum disorder, and behavior problems. The individuals did not consistently display dysmorphic features, congenital anomalies, or growth abnormalities. DNA methylation analysis revealed a weak DNAm profile for the cases with 9q34.3 duplication encompassing EHMT1, which could segregate the majority of the affected cases from controls. This study shows that individuals with 9q34.3 duplications including EHMT1 gene present with mild non-syndromic neurodevelopmental disorders and DNA methylation changes different from Kleefstra syndrome.

[Genetic analysis of a Chinese pedigree affected with overgrowth syndrome due to a small supernumerary marker chromosome].

OBJECTIVE: To carry out genetic analysis for a Chinese pedigree affected with intellectual disability and overgrowth due to a supernumerary marker chromosome (sSMC). METHODS: A pedigree which had presented at Jiaxing Maternity and Child Health Care Hospital on August 31, 2021 was selected as the study subject, for which chromosomal karyotyping, single nucleotide polymorphism-based microarray (SNP-array), and fluorescence in situ hybridization (FISH) were carried out in combination. RESULTS: SNP-array analysis showed that the proband and his sister had both harbored a 16.1 Mb duplication which encompassed the critical region of 15q26 overgrowth syndrome. FISH confirmed that the proband was 47,XX,+neo(15)(qter→q25.3:)mat, her mother was 47,XX,del(15)(q25.3:),+neo(15)(qter→q25.3:), whilst her father was normal. CONCLUSION: Application of multiple genetic techniques has facilitated delineation of the origin of sSMC and reliable genetic counseling for this pedigree.

[Guideline for the application of chromosomal microarray analysis in prenatal diagnosis (2023)].

After the promulgation of the first edition of expert consensus on the application of chromosomal microarray analysis (CMA) technology in prenatal diagnosis in 2014, after 8 years of clinical and technical development, CMA technology has become a first-line diagnosis technology for fetal chromosome copy number deletion or duplication abnormalities, and is widely used in the field of prenatal diagnosis in China. However, with the development of the industry and the accumulation of experience in case diagnosis, the application of CMA technology in many important aspects of prenatal diagnosis, such as clinical diagnosis testimony, data analysis and genetic counseling before and after testing, needs to be further standardized and improved, so as to make the application of CMA technology more in line with clinical needs. The revision of the guideline was led by the National Prenatal Diagnostic Technical Expert Group, and several prenatal diagnostic institutions such as Peking Union Medical College Hospital were commissioned to write, discuss and revise the first draft, which was discussed and reviewed by all the experts of the National Prenatal Diagnostic Technical Expert Group, and was finally formed after extensive review and revision. This guideline is aimed at the important aspects of the application of CMA technology in prenatal diagnosis and clinical diagnosis, from the clinical application of evidence, test quality control, data analysis and interpretation, diagnosis report writing, genetic counseling before and after testing and other work specifications are elaborated and introduced in detail. It fully reflects the integrated experience, professional thinking and guidance of the current Chinese expert team on the prenatal diagnosis application of CMA technology. The compilation of the guideline for the application of CMA technology in prenatal diagnosis will strive to promote the standardization and advancement of prenatal diagnosis of fetal chromosome diseases in China.

A Case of Class I 17p13.3 Microduplication Syndrome with Unilateral Hearing Loss.

17p13 is a chromosomal region characterized by genomic instability due to high gene density leading to multiple deletion and duplication events. 17p13.3 microduplication syndrome is a rare condition, reported only in 40 cases worldwide, which is found in the Miller-Dieker chromosomal region, presenting a wide range of phenotypic manifestations. Usually, the duplicated area is de novo and varies in size from 1.8 to 4.0 Mbp. Critical genes for this region are PAFAH1B1 (#601545), YWHAE (#605066), and CRK (#164762). 17p13.3 microduplication syndrome can be categorized into two classes (Class I and Class II) based on the genes that are present in the duplicated area, which lead to different phenotypes. In this report, we present a new case of Class I 17p13.3 microduplication syndrome that presents with unilateral sensorineural hearing loss. Oligonucleotide and SNP array comparative genomic hybridization (a-CGH) analysis revealed a duplication of approximately 121 Kbp on chromosome 17p13.3, which includes YWHAE and CRK genes. Whole-exome sequencing (WES) analysis confirmed the duplication. Our patient has common clinical symptoms of Class I 17p13.3 microduplication syndrome, and in addition, she has unilateral sensorineural hearing loss. Interestingly, WES analysis did not detect any mutations in genes that are associated with hearing loss. The above findings lead us to propose that hearing loss is a manifestation of 17p13.3 duplication syndrome.

Large Chromosome 2p Duplication-Associated Mechanisms and Clinical Presentations.

Chromosome 2p (chr2p) duplication, also known as trisomy 2p, is a rare chromosome abnormality associated with developmental delay, intellectual disability, behavioral problems, and distinctive facial features. Most of the reported cases involving trisomy 2p include additional copy number variants (CNVs) in other regions of the genome and are usually small in size. Little is known about the clinical outcomes of large duplications of chr2p as the sole cytogenetic abnormality. In this study, 193 samples at the Greenwood Genetic Center (GGC) with CNVs involving chr2p were evaluated, out of which 86 had chr2p duplications. Among them, 8 patients were identified with large chr2p duplications ranging in size from 9.3 Mb to 89 Mb, and no deletions or duplications involving other chromosomes were identified in those patients. These duplications were associated with inverted duplication, tandem duplication, and duplication as the result of translocation, with no additional CNVs identified by microarray analysis. Confirmation by conventional cytogenetics was performed in 7 of the 8 patients, and the translocations were confirmed by fluorescence in situ hybridization. Interestingly, 1 patient was found to have mosaic complete trisomy 2p as the result of an unbalanced de novo (X;2) chromosomal translocation. X-inactivation was skewed toward the derivative X chromosome, yet it did not appear to extend into the chromosome 2 material. Various shared clinical manifestations were observed in the individuals in this study, including developmental delay, hemifacial hypoplasia, cleft palate, and short stature, and they also have distinct features such as hypotonia, cerebellar hypogenesis, and corpus callosum agenesis, which might result from a gene dosage effect of the duplication. In conclusion, single-event large chr2p duplications can result from different mechanisms, including inverted or tandem duplications within chromosome 2, or translocations involving chromosome 2 and other chromosomes. Partial or complete trisomy 2p is commonly associated with developmental delay, and additional clinical features may be related to gene dosage effects.

Phenotypic shift in copy number variants: Evidence in 16p11.2 duplication syndrome.

PURPOSE: Recurrent 16p11.2 duplications produce a wide range of clinical outcomes with varying effects on cognition and social functioning. Family-based studies of copy number variants (CNVs) have revealed significant contributions of genomic background on variable expressivity. In this study, we measured the phenotypic effect of 16p11.2 duplications and quantified the modulating effect of familial background on cognitive and social outcomes. METHODS: Genomic and clinical data were ascertained from 41 probands with a 16p11.2 duplication and their first-degree relatives. Paired comparisons were completed to determine the duplication's effect on expected vs actual performance on standardized tests of intelligence (IQ) and social functioning (Social Responsiveness Scale-2). Intraclass correlations between relatives and probands were also calculated. RESULTS: Cognitive and social functioning were significantly lower among individuals with 16p11.2 duplications than their CNV-negative relatives, whereas intraclass correlations between the groups remained high for full-scale IQ and Social Responsiveness Scale-2 scores. CONCLUSION: The 16p11.2 duplication confers deleterious effects on cognition and social functioning, whereas familial background significantly influences phenotypic expression of these traits. Understanding variable expressivity in CNV disorders has implications for anticipatory clinical care, particularly for individuals who receive a genetic diagnosis at an early age, long before the full scope of manifestations becomes evident.

A unique coincidence of a 17q12 deletion and duplication in a Czech family led to a refined genotype-phenotype correlation.

Chromosomal band 17q12 is a gene-rich region flanked by segmental duplications, making the region prone to deletions and duplications via the non-allelic homologous recombination mechanism. While deletions cause a well-described disorder with a specific phenotype called renal cysts and diabetes mellitus, the phenotype caused by reciprocal duplications is less specific, primarily because of variable expressivity, and incomplete penetrance. We present an unusual family with four children carrying the 17q12 microduplication inherited from their clinically healthy mother, who was a carrier of both the duplication and, interestingly, also of an atypical deletion of the 17q12 region. The duplication was inherited from her diabetic father and the deletion from her diabetic mother who also suffered from a renal disorder. Clinical manifestations in the family were variable, but all children showed some degree of a neurodevelopmental disorder, such as epilepsy, intellectual disability, delayed speech development, or attention deficit disorder. The simultaneous occurrence of a deletion and duplication in the same chromosomal region in one family is very rare, and to our knowledge, individuals carrying both a deletion and a duplication of this region have never been described.

5p13 microduplication in a malformed fetus and his unaffected father.

The 5p13 microduplication syndrome is a contiguous gene syndrome characterized by developmental delay intellectual disability, hypotonia, unusual facies with marked variability, mild limb anomalies, and in some cases brain malformations. The duplication ranges in size from 0.25 to 1.08 Mb and encompasses five genes (NIPBL, SLC1A3, CPLANE1, NUP155, and WDR70), of which NIPBL has been suggested to be the main dose sensitive gene. All patients with duplication of the complete NIPBL gene reported thus far have been de novo. Here, we report a 25-week-old male fetus with hypertelorism, wide and depressed nasal bridge, depressed nasal tip, low-set ears, clenched hands, flexion contracture of elbows, knees, and left wrist, and bilateral clubfeet, bowing and shortening of long bones and brain malformation of dorsal part of callosal body. The fetus had a 667 kb gain at 5p13.2 encompassing SLC1A3, NIPBL and exons 22-52 of CPLANE1. The microduplication was inherited from the healthy father, in whom no indication for mosaicism was detected. The family demonstrates that incomplete penetrance of 5p13 microduplication syndrome may occur which is important in genetic counseling of families with this entity.

Guideline for the application of chromosomal microarray analysis in prenatal diagnosis (2023) / 中华妇产科杂志

After the promulgation of the first edition of expert consensus on the application of chromosomal microarray analysis (CMA) technology in prenatal diagnosis in 2014, after 8 years of clinical and technical development, CMA technology has become a first-line diagnosis technology for fetal chromosome copy number deletion or duplication abnormalities, and is widely used in the field of prenatal diagnosis in China. However, with the development of the industry and the accumulation of experience in case diagnosis, the application of CMA technology in many important aspects of prenatal diagnosis, such as clinical diagnosis testimony, data analysis and genetic counseling before and after testing, needs to be further standardized and improved, so as to make the application of CMA technology more in line with clinical needs. The revision of the guideline was led by the National Prenatal Diagnostic Technical Expert Group, and several prenatal diagnostic institutions such as Peking Union Medical College Hospital were commissioned to write, discuss and revise the first draft, which was discussed and reviewed by all the experts of the National Prenatal Diagnostic Technical Expert Group, and was finally formed after extensive review and revision. This guideline is aimed at the important aspects of the application of CMA technology in prenatal diagnosis and clinical diagnosis, from the clinical application of evidence, test quality control, data analysis and interpretation, diagnosis report writing, genetic counseling before and after testing and other work specifications are elaborated and introduced in detail. It fully reflects the integrated experience, professional thinking and guidance of the current Chinese expert team on the prenatal diagnosis application of CMA technology. The compilation of the guideline for the application of CMA technology in prenatal diagnosis will strive to promote the standardization and advancement of prenatal diagnosis of fetal chromosome diseases in China.

Genetic analysis of a Chinese pedigree affected with overgrowth syndrome due to a small supernumerary marker chromosome / 中华医学遗传学杂志

OBJECTIVE@#To carry out genetic analysis for a Chinese pedigree affected with intellectual disability and overgrowth due to a supernumerary marker chromosome (sSMC).@*METHODS@#A pedigree which had presented at Jiaxing Maternity and Child Health Care Hospital on August 31, 2021 was selected as the study subject, for which chromosomal karyotyping, single nucleotide polymorphism-based microarray (SNP-array), and fluorescence in situ hybridization (FISH) were carried out in combination.@*RESULTS@#SNP-array analysis showed that the proband and his sister had both harbored a 16.1 Mb duplication which encompassed the critical region of 15q26 overgrowth syndrome. FISH confirmed that the proband was 47,XX,+neo(15)(qter→q25.3:)mat, her mother was 47,XX,del(15)(q25.3:),+neo(15)(qter→q25.3:), whilst her father was normal.@*CONCLUSION@#Application of multiple genetic techniques has facilitated delineation of the origin of sSMC and reliable genetic counseling for this pedigree.

Prenatal diagnosis and molecular cytogenetic characterization of a de novo duplication of 2q12.2→q13 encompassing MALL, NPHP1, RGPD6 and BUB1.

OBJECTIVE: We present prenatal diagnosis and molecular cytogenetic characterization of a de novo duplication of 2q12.2→q13 encompassing MALL, NPHP1, RGPD6 and BUB1. CASE REPORT: A 36-year-old, primigravid woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XX,dup(2) (q12.2q13). Simultaneous array comparative genomic hybridization (aCGH) analysis revealed a 6.1-Mb 2q12.2q13 duplication. aCGH analysis of the parental bloods did not find such a duplication. Prenatal ultrasound was unremarkable. After genetic counseling, the parents decided to terminate the pregnancy at 21 weeks of gestation, and a 420-g female fetus was delivered with no gross abnormalities. Postnatal cytogenetic analysis of the umbilical cord confirmed the prenatal diagnosis. The parental karyotypes were normal. aCGH analysis of the umbilical cord revealed the result of arr [GRCh37 (hg19)] 2q12.2q13 (107, 132, 950-113,065,779) × 3.0 with a 2q12.2→q13 duplication encompassing 20 OMIM genes including MALL, NPHP1, RGPD6 and BUB1. Polymorphic DNA marker analysis of quantitative fluorescence polymerase chain reaction (QF-PCR) on the DNAs extracted from the umbilical cord and parental bloods confirmed a maternal origin of the duplication of 2q12.2→q13. CONCLUSION: Amniocentesis may incidentally detect a de novo chromosomal segmental duplication of maternal origin in the fetus. The genetic information acquired by molecular analyses such as aCGH and QF-PCR are useful for genetic counseling under such a circumstance.

Neurodevelopmental functioning in probands and non-proband carriers of 22q11.2 microduplication.

Microduplication of the LCR22-A to LCR22-D region on chromosome 22q11.2 is a recurrent copy number variant found in clinical populations undergoing chromosomal microarray, and at lower frequency in controls. Often inherited, there is limited data on intellectual (IQ) and psychological functioning, particularly in those individuals ascertained through a family member rather than because of neurodevelopmental disorders. To investigate the range of cognitive-behavioral phenotypes associated with 22q11.2 duplication, we studied both probands and their non-proband carrier relatives. Twenty-two individuals with 22q11.2 duplication (10 probands, 12 non-proband carriers) were prospectively assessed with a battery of neuropsychological tests, physical examination, and medical record review. Assessment measures with standardized norms included IQ, academic, adaptive, psychiatric, behavioral, and social functioning. IQ and academic skills were within the average range, with a trend toward lower scores in probands versus non-probands. Adaptive skills were within age expectations. Prevalence of attention deficits (probands only) and anxiety (both groups) was high compared with norms. The prevalence of autism spectrum disorder was relatively low (5% of total sample). Assessment of both probands and non-probands with 22q11.2 duplication suggests that the phenotypic spectrum with respect to neurodevelopment overlaps significantly with the general population. IQ and academic abilities are in the average range for most of the individuals with 22q11.2 duplication in our study, regardless of ascertainment as a proband or non-proband relative. Symptoms of attention deficit and anxiety were identified, which require further study. Results of this study further clarify the phenotype of individuals with 22q11.2 duplication, and provides important information for genetic counseling regarding this recurrent copy number variant.

Clinical and genetic study of three families with 15q11q13 duplications.

OBJECTIVE: To report three families with chromosome 15q11q13 duplications. CASE REPORT: We report the prenatal diagnosis and genetic counseling of three 15q11q13 duplications. CONCLUSION: Chromosomal microdeletions and microduplications are difficult to be detected by conventional cytogenetics. With molecular genetic techniques including array-based methods, the number of reported cases has rapidly increased. An integration of prenatal ultrasound, NIPT, karyotype analysis, CMA and genetic counseling is helpful for the prenatal diagnosis of chromosomal microdeletions/microduplications.

Prenatal diagnosis of de novo int22h1/int22h2-mediated Xq28 duplication syndrome involving RAB39B following a previous ambiguous genitalia pregnancy.

OBJECTIVE: To report a prenatal diagnosis of int22h1/int22h2-mediated Xq28 duplication syndrome. CASE REPORT: Herein, we present the case of a 28-year-old female who had a previous ambiguous genitalia pregnancy without genetic abnormality that was terminated at 23+2 weeks of gestation. The fetus of the current pregnancy harbored a de novo copy number variation at the Xq recurrent region (int22h1/int22h2-flanked; including the RAB39B gene) with a 0.397 Mb microduplication. The literature suggests the clinical manifestation of int22h1/int22h2-mediated Xq28 duplication syndrome tends to show a milder clinical phenotype in females than males. Although the fetus in this case was female, taking into consideration the parents' age and culture, the family decided to terminate this pregnancy due to the genetic abnormality. CONCLUSION: Prenatally diagnosed de novo int22h-1/int22h-2-mediated Xq28 duplication syndrome exhibits variable phenotypic traits in female fetuses.

Novel findings, mini-review and dysmorphological characterization of 16p13.11 microduplication syndrome.

The short arm of chromosome 16 and especially the region 16p13.11 is a chromosome region where many structural variants, especially deletions and duplications, can be observed. Although deletions of this region are clinically well defined, duplications are rare, and so far, there is no established clinical consensus in regard with its clinical picture, and especially the dysmorphic perspective of the disease is far from being clear. A 5-year-and-2-month-old patient who presented with epilepsy, autism and late speech onset complaints was evaluated in our genetics department. On physical examination, unilateral preauricular skin tag and upslanting palpebral fissures were noted. Microarray analysis was performed and reported as ([hg19]: 16p13.11 (14.897.804-16.730.375) x3). The literature review revealed only a few reports about the syndrome, but some dysmorphological findings appear to recur in different reports, which enables a possible characterization. Dysmorphic findings were discussed.

Cerebral white matter abnormalities associated with chromosome 18q duplication.

BACKGROUND: Chromosome 18q duplications are associated with a range of phenotypes often similar to complete trisomy 18, variably including poor growth, feeding difficulties, congenital malformations and dysmorphic facial features. Although 18q duplication patients may have seizures and developmental impairment, brain MRI typically shows only variable degrees of cerebral atrophy. PATIENT: We present a boy with a 52.2 Mb 18q duplication in whom brain MRI in the neonatal period showed striking white matter abnormalities, most notable in the frontal lobes. His clinical presentation was otherwise in keeping with trisomy 18, including characteristic facial features, hypotonia, cardiac malformation, rocker bottom feet, pectus excavatum, short and broad thumbs and halluces, and diabetes insipidus. CONCLUSION: Since not previously reported in association with 18q duplication, the observation of cerebral white matter anomalies is particularly interesting. This radiologic pattern is a well-recognized feature of 18q deletion syndrome, hypothesized by many to occur due to haploinsufficiency of MBP, the gene encoding myelin basic protein. The mechanisms leading to the white matter anomalies in this patient remain unexplained.