Proximal microdeletions and microduplications of 1q21.1 contribute to variable abnormal phenotypes

Rosenfeld, Jill A.; Traylor, Ryan N; Schaefer, Gerald; McPherson, Elizabeth; Ballif, Blake C.; Klopocki, Eva; Mundlos, Stefan; Shaffer, Lisa G.; Aylsworth, Arthur S.

doi:10.1038/ejhg.2012.6

Cited by 83 publications

(112 citation statements)

References 55 publications

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“…There is little information in the published cases regarding dimensional assessment of functioning, rendering comparison to our findings difficult. Previously reported duplication cases have similar rates as deletion cases of ASD diagnosis 6 and developmental delay, 1,2 suggesting, at least at the categorical level, the deleterious impact of both CNVs is sufficient to cross diagnostic thresholds and neither emerges as more impairing.…”

Section: Discussionmentioning

confidence: 72%

“…The observed high frequency of ASD and other associated developmental abnormalities in the duplication cases is consistent with previous findings. 2,6,12 In the Figure 2 Dimensional assessment of participants. Relationship between overall cognitive ability, proband status, and age in the cohort showing that the proband children in both the deletion and duplication groups had a greater range of cognitive abilities that extended into the impaired range, whereas the adults, identified through cascade testing, had cognitive abilities that spanned the average to above average range.…”

Section: Discussionmentioning

confidence: 99%

“…1,3,8 Although both deletions and duplications have been reported in individuals with schizophrenia and ASD, deletions have been more strongly associated with schizophrenia than duplications [9][10][11][12] and duplications more strongly associated with ASD/autistic features than deletions. 2,3,6,8 Most studies of 1q21.1 have reported on individuals ascertained through disease-specific series, e.g., work performed by The International Schizophrenia Consortium (2008) and Levinson et al 9,12 Studies of patients ascertained from genetics clinics [1][2][3]6 provide a broader understanding of the full range of the clinical phenotype but are limited in the availability of standardized, dimensionally assessed behavioral and psychiatric features.…”

Section: Introductionmentioning

confidence: 99%

“…This is due, in part, to the rarity of specific CNVs limiting sample sizes, and also because of differing ascertainment approaches, rendering equivalent comparisons impossible. The detailed characterization of , LeeAnne Green Snyder, PhD 6,10 , Sarah Spence, MD 11 , Melissa B. Ramocki, MD 12 , David W. Evans, PhD 13 , John E. Spiro, PhD 10 , Christa L. Martin, PhD 13,14 , David H. Ledbetter, PhD 13,14 and Wendy K. Chung, MD 15,16 ; on behalf of the Simons VIP consortium.…”

Section: Introductionmentioning

confidence: 99%

“…Deletions and duplications at the 1q21.1 locus are more frequent in clinical series of individuals with intellectual disability, developmental delay, schizophrenia, and autism spectrum disorder (ASD) compared with controls. [1][2][3][4][5][6][7] Phenotypes associated with 1q21.1 also include other psychiatric diagnoses such as learning disabilities, attention-deficit hyperactivity disorder (ADHD), bipolar disorder, anxiety, and depression. 1,3,8 Although both deletions and duplications have been reported in individuals with schizophrenia and ASD, deletions have been more strongly associated with schizophrenia than duplications [9][10][11][12] and duplications more strongly associated with ASD/autistic features than deletions.…”

Section: Introductionmentioning

confidence: 99%

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Clinical phenotype of the recurrent 1q21.1 copy-number variant

Bernier

Steinman

Reilly

et al. 2016

Genetics in Medicine

139

163

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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.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Clinical phenotype of the recurrent 1q21.1 copy-number variant

Bernier

Steinman

Reilly

et al. 2016

Genetics in Medicine

139

163

View full text Add to dashboard Cite

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Less common underlying genetic diagnoses found in a cohort of 139 individuals surgically corrected for craniosynostosis

Ittleman

Mckissick

Bosanko

et al. 2017

American J of Med Genetics Pt A

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Craniosynostosis is the premature ossification and fusion of one or more cranial sutures. It is one of the most common craniofacial anomalies, occurring in one in 2,000-2,500 births (Boulet, Rasmussen, & Honein, 2008). The multifactorial etiology of craniosynostosis involving both genetic and environmental factors results in a heterogeneous group of disorders (Heuze, Holmes, Peter, c Denominator represents those with phenotypic features described. ITTLEMAN ET AL. | 489 and maxilla-facial computed-tomography (CT) scans revealed metopic craniosynostosis while his alkaline phosphatase levels were low (49, Normal 129-291 U/L). ALPL gene sequencing confirmed the clinical suspicion of hypophosphatasia (HPP) (compound heterozygous c.526G>A/c.1250A>G, p.(Ala176Thr)/p.(Asn417Ser)) and CVR was performed at 18 months of age prior to initiation of enzyme replacement therapy. Craniosynostosis is a known feature of HPP, particularly the infantile type (Mornet, 2007). Individual CS#50 was first evaluated in the neonatal period for craniofacial dysmorphism and skeletal anomalies. Radiographic images documented markedly advanced bone age, widening of the proximal and middle phalanges, and severe cervical spinal stenosis. This patient underwent CVR for sagittal suture synostosis and posterior laminectomies of C3-C4 for cervical stenosis at 2 and 4 years of age, respectively. Over time, the patient was noted to have a flat midface, prominent forehead, full lips, and shallow orbits. The clinical diagnosis of Marshall-Smith syndrome was made and while molecular cytogenetic microarray was normal, sequencing of the NFIX gene could not be conducted. Craniosynostosis was reported in 5/38 (13%) of patients with Marshall-Smith syndrome in a previous study (Shaw et al., 2010).The implications of genetic testing have impact on the surgeon's discussion with the family prior to discussing surgical repair. It is well known, for example, that children with syndromic craniosynostosis tend to have higher relapse rates of their cranial dysmorphology, increased intra-cranial pressure and higher re-operative rates that their non-syndromic cohorts (Esparza et al., 2008;McCarthy et al., 1995). In agreement with a previous report of a large cohort of children with surgically repaired craniosynostosis, in this study, when comparing individuals with proven syndromic craniosynostosis to all others, there was a higher rate of multiple sutures affected (70 vs. 17%, p = < 0.000001) and need for several surgical procedures (48 vs. 25%, p = < 0.05), most of which were invasive ( Supplementary Table S3) (Wilkie et al., 2010). Likewise, the overall rates of suspicion for syndromic craniosynostosis (56/139, 40%) and identified underlying genetic diagnoses (27/56, 48%) are comparable to previous data by Wilkie et al. (2010) of 37% (122/326) and 60% (73/122), respectively. The present study does have some limitations. While a systematic evaluation was conducted by the initial provider evaluating the individual with craniosynostosis, a genetic evaluation was not ...

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

Edwards

Schulze

Rosenfeld

et al. 2021

American J of Med Genetics Pt A

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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.

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Proximal microdeletions and microduplications of 1q21.1 contribute to variable abnormal phenotypes

Cited by 83 publications

References 55 publications

Clinical phenotype of the recurrent 1q21.1 copy-number variant

Clinical phenotype of the recurrent 1q21.1 copy-number variant

Less common underlying genetic diagnoses found in a cohort of 139 individuals surgically corrected for craniosynostosis

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

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