Pseudoarthrosis of the clavicle and copper beaten skull associated with chromosome 10p11.21p12.1 microdeletion

Shahdadpuri, Raveen; Vries, Bert de; Pfundt, Rolph; Leeuw, Nicole de

doi:10.1002/ajmg.a.32088

Cited by 25 publications

(33 citation statements)

References 30 publications

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“…Our six patients share some features with the previously described patient with a 10p12-p11 deletion. 5 Clinical data for this patient are summarised in Table 1 (genomic data kindly provided by Dr Nicole de Leeuw chr10: 26.901.972-36.934.901 (hg18)). The similarities between our six patients and the patient reported in the literature included DD and a majority of the patients have abnormal behaviour and dysmorphic features, including bulbous nasal tip, deep set eyes, synophrys/thick eyebrows and full cheeks, whereas other features varied.…”

Section: Molecular Results Of the Six Patients Are Summarised Inmentioning

confidence: 99%

“…There is one previous report of a patient with DD and dysmorphic features presenting with a microdeletion within this region detected with arrayCGH. 5 The seven patients share some phenotypic traits and dysmorphic features. We describe the phenotypic traits that are shared between all individuals and suggest that microdeletions of 10p12.31p11.21 might be associated with a new clinically recognisable microdeletion syndrome.…”

Section: Introductionmentioning

confidence: 99%

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Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11

et al. 2011

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International audienceWith the clinical implementation of genomic microarrays, the detection of cryptic unbalanced rearrangements in patients with syndromic developmental delay has considerably improved. Here we report the molecular karyotyping and phenotypic description of six new unrelated patients with partially overlapping microdeletions at 10p12.31p11.21 ranging from 1.0 Mb to 10.6 Mb. The smallest region of overlap is 306 kb, which includes gene, known to be associated with microtubule function and to play a role in cell division. Another patient has previously been described with a 10 Mb deletion, partially overlapping with our six patients. All seven patients have developmental delay and a majority of the patients have abnormal behaviour and dysmorphic features including bulbous nasal tip, deep set eyes, synophrys/thick eyebrows, and full cheeks, while other features varied. All patients also displayed various visual impairments and 6 out of 7 patients had cardiac malformations. Together with the previously reported patient, our study suggests that the detected deletions may represent a new contiguous gene syndrome caused by dosage sensitive genes that predispose to developmental delay

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Section: Molecular Results Of the Six Patients Are Summarised Inmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11

et al. 2011

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“…(b) The genomic region involved in the 10p12p11 contiguous gene deletion region with the previously published microdeletions, represented by gray horizontal bars. [14][15][16] (c) Detailed view of the smallest region of overlap (SRO) and the deletion described in this study, represented by a red horizontal bar. In addition, de novo mutations in WAC (NM_016628.3) reported in this study are shown according to their relative position at protein level.…”

Section: Identification Of Individuals With De Novo Cnvs Affecting Wacmentioning

confidence: 99%

“…The shortest region of deletion overlap of the chromosome 10p12p11 contiguous gene deletion syndrome was previously determined by nine deletions ranging in size between 0.99 and 10.66 Mb. [14][15][16][17] Comparison of the deletion in Individual 2 to the shortest region of deletion overlap indicates WAC as a only remaining candidate gene for the ID phenotype (Figure 1b).…”

Section: Identification Of Individuals With De Novo Cnvs Affecting Wacmentioning

confidence: 99%

“…All individuals with a deletion of at least these two genes were reported to have a similar phenotype including ID, behavior problems and dysmorphic features, supporting a disease cause of WAC heterozygous loss-offunction. [14][15][16][17] Although it may well be hypothesized that WAC haploinsuffiency may explain the ID phenotype observed in the 10p12p11 contiguous gene syndrome, and ID in individuals with mutations in this gene, detailed evidence to support this hypothesis is lacking. In the present study we aimed to identify additional individuals with de novo mutations in WAC by using different sequencing strategies to define the clinical spectrum associated with WAC haploinsufficiency.…”

Section: Introductionmentioning

confidence: 99%

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De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

et al. 2016

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Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.

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Interstitial 10p11.23–p12.1 microdeletions associated with developmental delay, craniofacial abnormalities, and cryptorchidism

Mroczkowski

Arnold

Schneck

et al. 2014

American J of Med Genetics Pt A

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Cryptorchidism is the most common genital problem encountered in males and is associated with many chromosomal disorders; however, the genetic factors are mostly unknown. To delineate critical genes affecting testicular migration, we performed genotype-phenotype correlation in patients with deletions involving the proximal short arm of chromosome 10 (10p11-p12), a rare abnormality characterized by developmental delay, craniofacial abnormalities, and in some cases, cryptorchidism. Here we report on a male patient with developmental delay, mild craniofacial dysmorphism, bilateral cryptorchidism, and an 850-kb deletion, within the 10p11.2 region, involving three genes-MKX, ARMC4, and MPP7-as determined by array comparative genomic hybridization analysis. Comparison with four previously reported male patients with overlapping deletions revealed a 140-kb common region, containing the MKX gene, in association with cryptorchidism. The MKX gene is a member of the three amino acid loop extension (TALE) superclass of homeobox genes that is expressed in developing male gonads (male gonadal ridge and testis cords) in temporal relationship to SOX9, a critical regulator of sexual differentiation. Our results suggest that haploinsufficiency of the MKX gene may affect the developmental process during testis migration or serve as a genetic susceptibility locus for cryptorchidism. We propose that deletions of the proximal 10p represent a contiguous gene syndrome; therefore, patients may present with a complex phenotype, depending on the extent of the deletion.

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Pseudoarthrosis of the clavicle and copper beaten skull associated with chromosome 10p11.21p12.1 microdeletion

Cited by 25 publications

References 30 publications

Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11

Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

Interstitial 10p11.23–p12.1 microdeletions associated with developmental delay, craniofacial abnormalities, and cryptorchidism

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