A microdeletion encompassing <i>PHF21A</i> in an individual with global developmental delay and craniofacial anomalies

Labonne, Jonathan D J; Vogt, Julie; Reali, Lisa; Kong, Il-Keun; Layman, Lawrence C.; Kim, Hyung Goo

doi:10.1002/ajmg.a.37344

Cited by 17 publications

(27 citation statements)

References 22 publications

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“…These cases provide direct evidence supporting PHF21A haploinsufficiency as a cause of ID and CFA. PSS shows variable clinical features: ASD, epilepsy, overgrowth, and micropenis [3][4][5]9]. While associations between a deleted gene and clinical features have not been well defined, the cases presented here, with PHF21A-truncating variants, give insight regarding the PSS features that are attributed to PHF21A haploinsufficiency.…”

Section: Variant Screeningmentioning

confidence: 82%

“…However, its involvement has not been confirmed because the overlapping regions of the deletions (ID/CFA/overgrowth locus in Fig. 1a) [4,9]. Moreover, gross deletions and translocations might have position effects on surrounding genes [6].…”

Section: Variant Screeningmentioning

confidence: 98%

“…PSS is clinically characterized by intellectual disability (ID), craniofacial anomalies (CFA), parietal foramina, and multiple exostoses [1,2]. PSS occasionally displays autism spectrum disorders (ASD) [3], epilepsy [3], overgrowth (increased weight, length, and/or head circumference [HC]) [4,5], and micropenis [4,6]. The minimum deleted region contains at least five genes [4].…”

Section: Introductionmentioning

confidence: 99%

“…PSS occasionally displays autism spectrum disorders (ASD) [3], epilepsy [3], overgrowth (increased weight, length, and/or head circumference [HC]) [4,5], and micropenis [4,6]. The minimum deleted region contains at least five genes [4]. Some clinical features in PSS can be explained by variants affecting function in two genes; in ALX4 (MIM 605420) causing enlarged parietal foramina, and in EXT2 (MIM 608210) causing multiple exostoses [7,8].…”

Section: Introductionmentioning

confidence: 99%

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De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies

Hamanaka

Sugawara

Shimoji³

et al. 2018

Eur J Hum Genet

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Potocki-Shaffer syndrome (PSS) is a contiguous gene syndrome caused by 11p11.2 deletions. PSS is clinically characterized by intellectual disability, craniofacial anomalies, enlarged parietal foramina, and multiple exostoses. PSS occasionally shows autism spectrum disorder, epilepsy, and overgrowth. Some of the clinical features are thought to be associated with haploinsufficiency of two genes in the 11p11.2 region; variants affecting the function of ALX4 cause enlarged parietal foramina and EXT2 lead to multiple exostoses. However, the remaining clinical features were still yet to be linked to specific genetic alterations. In this study, we identified de novo truncating variants in an 11p11.2 gene, PHF21A, in three cases with intellectual disability and craniofacial anomalies. Among these three cases, autism spectrum disorder was recognized in one case, epilepsy in one case, and overgrowth in two cases. This study shows that PHF21A haploinsufficiency results in intellectual disability and craniofacial anomalies and possibly contributes to susceptibility to autism spectrum disorder, epilepsy, and overgrowth, all of which are PSS features.

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Section: Variant Screeningmentioning

confidence: 82%

Section: Variant Screeningmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies

Hamanaka

Sugawara

Shimoji³

et al. 2018

Eur J Hum Genet

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“…Among these, we identify an excess of recurrent missense mutation in MAPK3 mapping to the 16p11.2 microdeletion/microduplication region associated with autism and ID 65 . Recurrent LGD mutations in PHF21A, a gene previously implicated by translocations and focal CNVs 66,67 , map to the Potocki-Shaffer deletion region, while an excess of missense mutations in KIF1A correspond to the 2q37 deletion syndrome region 68,69 . Recurrent LGD DNMs in SIN3A, a REST and MECP2 interactor, map to the 15q24 deletion region 44,70,71 .…”

Section: Cnv Intersectionmentioning

confidence: 99%

Neurodevelopmental disease genes implicated byde novomutation and CNV morbidity

Coe

Stessman²,

Sulovari

et al. 2017

Preprint

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We combined de novo mutation (DNM) data from 10,927 cases of developmental delay and autism to identify 301 candidate neurodevelopmental disease genes showing an excess of missense and/or likely gene-disruptive (LGD) mutations. 164 genes were predicted by two different DNM models, including 116 genes with an excess of LGD mutations. Among the 301 genes, 76% show DNM in both autism and intellectual disability/developmental delay cohorts where they occur in 10.3% and 28.4% of the cases, respectively. Intersecting these results with copy number variation (CNV) morbidity data identifies a significant enrichment for the intersection of our gene set and genomic disorder regions (36/301, LR+ 2.53, p=0.0005). This analysis confirms many recurrent LGD genes and CNV deletion syndromes (e.g., KANSL1, PAFAH1B1, RA1, etc.), consistent with a model of haploinsufficiency. We also identify genes with an excess of missense DNMs overlapping deletion syndromes (e.g., KIF1A and the 2q37 deletion) as well as duplication syndromes, such as recurrent MAPK3 missense mutations within the chromosome 16p11.2 duplication, recurrent CHD4 missense DNMs in the 12p13 duplication region, and recurrent WDFY4 missense DNMs in the 10q11.23 duplication region. Finally, we also identify pathogenic CNVs overlapping more than one recurrently mutated gene (e.g., Sotos and Kleefstra syndromes) raising the possibility that multiple gene-dosage imbalances may contribute to phenotypic complexity of these disorders. Network analyses of genes showing an excess of DNMs confirm previous well-known enrichments but also highlight new functional networks, including cell-specific enrichments in the D1+ and D2+ spiny neurons of the striatum for both recurrently mutated genes and genes where missense mutations cluster.

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Potocki–Shaffer syndrome in a child without intellectual disability—The role of PHF21A in cognitive function

McCool

Spinks-Franklin

Noroski

et al. 2017

American J of Med Genetics Pt A

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Potocki-Shaffer syndrome is a contiguous gene deletion syndrome involving 11p11.2p12 and characterized by multiple exostoses, biparietal foramina, genitourinary anomalies in males, central nervous system abnormalities, intellectual disability, and craniofacial abnormalities. Current literature implicates haploinsufficiency of three genes (ALX4, EXT2, and PHF21A) in causing some of the cardinal features of PSS. We report a patient with multiple exostoses, biparietal foramina, and history of mild developmental delay. Cognitive and behavioral testing supported formal diagnoses of anxiety, verbal dyspraxia, articulation disorder, and coordination disorder, without intellectual disability. His facial features, though distinctive, were not typical of those observed in PSS. As the chromosomal deletion does not encompass PHF21A, this case lends further support that haploinsufficiency of PHF21A contributes to the intellectual disability and craniofacial abnormalities in PSS and that there are other genes in the region which likely contribute to the behavioral phenotype in this syndrome. © 2017 Wiley Periodicals, Inc.

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A microdeletion encompassing PHF21A in an individual with global developmental delay and craniofacial anomalies

Cited by 17 publications

References 22 publications

De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies

De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies

Neurodevelopmental disease genes implicated byde novomutation and CNV morbidity

Potocki–Shaffer syndrome in a child without intellectual disability—The role of PHF21A in cognitive function

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