Whole exome sequencing of families with 1q21.1 microdeletion or microduplication

Qiao, Ying; Badduke, Chansonette; Tang, Flamingo; Cowieson, David; Martell, Sally; Sm, Lewis; Peñaherrera, Maria S.; Robinson, Wendy P.; Volchuk, Allen; Rajcan‐Separovic, Evica

doi:10.1002/ajmg.a.38247

Cited by 10 publications

(7 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Findings from prior studies (Girirajan et al, 2010, 2012) suggest that the 1q21.1 microdeletion is a risk factor for neuropsychiatric phenotypes and congenital anomalies and that expression and penetrance of the variant may be influenced by additional genetic factors. Limited studies have investigated how variants throughout the genome may impact expression of the distal 1q21.1 deletion (Mefford et al, 2008; Qiao et al, 2017). Genome‐level analysis among carriers of the deletion is warranted to further delineate how genomic variation may impact the expression of the distal 1q21.1 deletion.…”

Section: Discussionmentioning

confidence: 99%

Clinical characterization of individuals with the distal 1q21.1 microdeletion

Edwards

Schulze

Rosenfeld

et al. 2021

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Distal 1q21.1 microdeletions have shown highly variable clinical expressivity and incomplete penetrance, with affected individuals manifesting a broad spectrum of nonspecific features. The goals of this study were to better describe the phenotypic spectrum of patients with distal 1q21.1 microdeletions and to compare the clinical features among affected individuals. We performed a retrospective chart review of 47 individuals with distal 1q21.1 microdeletions tested at a large clinical genetic testing laboratory, with most patients being clinically evaluated in the same children's hospital. Health information such as growth charts, results of imaging studies, developmental history, and progress notes were collected. Statistical analysis was performed using Fisher's exact test to compare clinical features among study subjects. Common features in our cohort include microcephaly (51.2%), seizures (29.8%), developmental delay (74.5%), failure to thrive (FTT) (68.1%), dysmorphic features (63.8%), and a variety of congenital anomalies such as cardiac abnormalities (23.4%) and genitourinary abnormalities (19.1%). Compared to prior literature, we found that seizures, brain anomalies, and FTT were more prevalent among our study cohort. Females were more likely than males to have microcephaly (p = 0.0199) and cardiac abnormalities (p = 0.0018). Based on existing genome‐wide clinical testing results, at least a quarter of the cohort had additional genetic findings that may impact the phenotype of the individual. Our study represents the largest cohort of distal 1q21.1 microdeletion carriers available in the literature thus far, and it further illustrates the wide spectrum of clinical manifestations among symptomatic individuals. These results may allow for improved genetic counseling and management of affected individuals. Future studies may help to elucidate the underlying molecular mechanisms impacting the phenotypic variability observed with this microdeletion.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinical characterization of individuals with the distal 1q21.1 microdeletion

Edwards

Schulze

Rosenfeld

et al. 2021

American J of Med Genetics Pt A

View full text Add to dashboard Cite

show abstract

“…However, there is no explanation as to why the same position and CNV would result in a different phenotype[ 19 ]. Genes are epigenetically inherited and subject to environmental modifications; genetic alterations may make CNV carriers more susceptible to environmental influences, which can lead to different phenotypes, depending on the severity of the environmental impact[ 20 , 21 ]. Furthermore, the variable expressivity and incomplete penetrance suggest that the influence of CNV is modified by other genetic loci or environmental factors[ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of 1q21.1 microduplication in a family: A case report

Huang¹,

Xu²,

Wang³

et al. 2023

World J Clin Cases

View full text Add to dashboard Cite

BACKGROUND Copy number variation (CNV) has become widely recognized in recent years due to the extensive use of gene screening in developmental disorders and epilepsy research. 1q21.1 microduplication syndrome is a rare CNV disease that can manifest as multiple congenital developmental disorders, autism spectrum disorders, congenital malformations, and congenital heart defects with genetic heterogeneity. CASE SUMMARY We reported a pediatric patient with 1q21.1 microduplication syndrome, and carried out a literature review to determine the correlation between 1q21.1 microduplication and its phenotypes. We summarized the patient’s medical history and clinical symptoms, and extracted genomic DNA from the patient, her parents, elder brother, and sister. The patient was an 8-mo-old girl who was hospitalized for recurrent convulsions over a 2-mo period. Whole exon sequencing and whole genome low-depth sequencing (CNV-seq) were then performed. Whole exon sequencing detected a 1.58-Mb duplication in the CHR1:145883867-147465312 region, which was located in the 1q21.1 region. Family analysis showed that the pathogenetic duplication fragment, which was also detected in her elder brother’s DNA originated from the mother. CONCLUSION Whole exon sequencing combined with quantitative polymerase chain reaction can provide an accurate molecular diagnosis in children with 1q21.1 microduplication syndrome, which is of great significance for genetic counseling and early intervention.

show abstract

“…The WES technology showed a great effectiveness in genetic etiology diagnosis in patients at the single-gene level, while few studies were available to further reveal the phenotypical diversity of unexplained structure variants using WES technology. Additional mutations besides the structural variants were identified by WES detection in patients with familial 1q21.1 microduplication/microdeletion, duplication of Xp22.31, and 16p11.2 duplication who exhibited phenotypical variability ( Dastan et al, 2016 ; Qiao et al, 2017 ; Qiao et al, 2019 ). In addition, a recent study conducted by Granata et al (2022 ) identified variants in CECR2 , MTOR , RICTOR, and LRRK2 genes by WES detection in the affected patients who also had a 16p13.11 microdeletion and proposed that WES technology could be used as a fundamental tool to identify additional mutations in patients with a predisposing variant.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Prenatal Whole-Exome Sequencing Identified a Novel Nonsense Mutation of the KCNH2 Gene in a Fetus With Familial 2q14.2 Duplication

Zhuang¹,

Chen

Wang³

et al. 2022

Front. Genet.

View full text Add to dashboard Cite

Background: Pathogenic mutations in the KCNH2 gene were associated with long QT syndrome 2 (LQT2), which typically manifest in a prolonged QT interval and may lead to recurrent syncopes, seizure, or sudden death. Limited reports indicated that the KCNH2 mutations would result in LQT2 combined with tetralogy of fallot. Our goal was to present an additional case of LQT2 combined with the tetralogy of fallot in a fetus with a novel KCNH2 mutation.Case presentation: Enrolled in this study was a 23-year-old pregnant woman from Quanzhou Fujian province, China. In her pregnancy, fetal ultrasound anomalies were identified, including tetralogy of fallot, coronary sinus enlargement, and persistent left superior vena cava. No chromosomal abnormality was detected by fetal karyotype analysis. However, 238.1-kb duplication in the 2q14.2 region containing the GLI2 gene was observed in the fetus by chromosomal array analysis, which was inherited from the mother with normal clinical features and interpreted as a variant of uncertain significance (VOUS). Furthermore, whole-exome sequencing (WES) detection identified a novel nonsense c.1907C > G (p.S636*) mutation in the KCNH2 gene in the fetus, and it was classified as a likely pathogenic variant, according to the ACMG guidelines. Parental verification analysis indicated that c.1907C > G (p.S636*) mutation was inherited from the mother.Conclusion: In this study, we believe that 2q14.2 duplication may not be the reason for fetal heart defects; moreover, we described an additional case with KCNH2 gene mutation, which may lead to LQTS and be associated with congenital heart defects. In addition, our study further confirms the application value of the WES technology in prenatal genetic etiology diagnosis of fetuses with structural anomalies and unexplained structural variants.

show abstract

Whole exome sequencing of families with 1q21.1 microdeletion or microduplication

Cited by 10 publications

References 47 publications

Clinical characterization of individuals with the distal 1q21.1 microdeletion

Clinical characterization of individuals with the distal 1q21.1 microdeletion

Identification of 1q21.1 microduplication in a family: A case report

Case Report: Prenatal Whole-Exome Sequencing Identified a Novel Nonsense Mutation of the KCNH2 Gene in a Fetus With Familial 2q14.2 Duplication

Contact Info

Product

Resources

About