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

Hamanaka, Kohei; Sugawara, Yuji; Shimoji, Takeyoshi; Nordtveit, Tone Irene; Kato, Mitsuhiro; Nakashima, Mitsuko; Saitsu, Hirotomo; Suzuki, Toshimitsu; Yamakawa, Kazuhiro; Aukrust, Ingvild; Houge, Gunnar; Mitsuhashi, Satomi; Takata, Atsushi; Iwama, Kazuhiro; Alkanaq, Ahmed; Fujita, Atsushi; Imagawa, Eri; Mizuguchi, Takeshi; Miyake, Noriko; Miyatake, Satoko; Matsumoto, Naomichi

doi:10.1038/s41431-018-0289-x

Cited by 16 publications

(31 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among three patients with ID and craniofacial anomalies, epilepsy was present in case 1, autism spectrum disorder (ASD) in case 2, and overgrowth with macrocephaly in cases 1 and 3. The authors have concluded that PHF21A haploinsufficiency results in ID and craniofacial anomalies, and possibly contributes to ASD, epilepsy, and overgrowth [8]. Here, we report seven individuals with heterozygous pathogenic sequence variants within the coding region of PHF21A and provide detailed clinical descriptions, further expanding the phenotype associated with PHF21A haploinsufficiency.…”

Section: Introductionmentioning

confidence: 71%

“…Although we reported that PHF21A was associated with ID and craniofacial anomalies by the positional cloning of two patients with balanced translocations in 2012 [4], no point mutations affecting this gene had been reported to confirm its deleterious impact until three patients with de novo truncating mutations were reported very recently [8], while this manuscript was being prepared. Taking into account that one out of the three reported patients has ASD [8], we also identified an additional three patients with ASD (patients 1, 5, and 7), further suggesting that PHF21A is a novel ASD gene. Patients 1 and 3 have very similar mutations, differing by only one amino acid, yet only patient 1 has ASD.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism

et al. 2019

View full text Add to dashboard Cite

BackgroundPHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in PHF21A were reported recently. Here, we analyze genomic data from seven unrelated individuals with mutations in PHF21A and provide detailed clinical descriptions, further expanding the phenotype associated with PHF21A haploinsufficiency.MethodsDiagnostic trio whole exome sequencing, Sanger sequencing, use of GeneMatcher, targeted gene panel sequencing, and MiSeq sequencing techniques were used to identify and confirm variants. RT-qPCR was used to measure the normal expression pattern of PHF21A in multiple human tissues including 13 different brain tissues. Protein-DNA modeling was performed to substantiate the pathogenicity of the missense mutation.ResultsWe have identified seven heterozygous coding mutations, among which six are de novo (not maternal in one). Mutations include four frameshifts, one nonsense mutation in two patients, and one heterozygous missense mutation in the AT Hook domain, predicted to be deleterious and likely to cause loss of PHF21A function. We also found a new C-terminal domain composed of an intrinsically disordered region. This domain is truncated in six patients and thus likely to play an important role in the function of PHF21A, suggesting that haploinsufficiency is the likely underlying mechanism in the phenotype of seven patients. Our results extend the phenotypic spectrum of PHF21A mutations by adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems. Furthermore, PHF21A is highly expressed in the human fetal brain, which is consistent with the neurodevelopmental phenotype.ConclusionDeleterious nonsense, frameshift, and missense mutations disrupting the AT Hook domain and/or an intrinsically disordered region in PHF21A were found to be associated with autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies. This suggests that PHF21A is involved in autism spectrum disorder and intellectual disability, and its haploinsufficiency causes a diverse neurological phenotype.Electronic supplementary materialThe online version of this article (10.1186/s13229-019-0286-0) contains supplementary material, which is available to authorized users.

show abstract

Section: Introductionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism

et al. 2019

View full text Add to dashboard Cite

show abstract

“…In previous works, we reported trigonocephaly, a form of craniosynostosis, in which the early closure of the metopic suture leads to a metopic ridge in patients affected with motor, learning and speech developmental delays 7,8 . In a collaborative work we have recently identified de novo truncating variants in PHF21A in three patients of NDD with macrocephaly and/or trigonocephaly 9 …”

Section: Introductionmentioning

confidence: 94%

“…Eight of those (SCN1A, IQSEC2, STXBP1, CACNA1E, ARID1B, DDX3X, WHSC1, PHF21A) have been known to be responsible for NDDs associated with IDs or epilepsies. 9,[20][21][22][23][24][25][26][27][28][29] The remaining nine (MSX2, CYP1A1, C14orf119, FLI1, CYB5R4, SEL1L2, RAB11FIP2, ZMYND8, and ZNF143) were novel for NDD so far to our knowledge.…”

Section: Identification Of Genes Mutated In Patients With Nddmentioning

confidence: 99%

“…7,8 In a collaborative work we have recently identified de novo truncating variants in PHF21A in three patients of NDD with macrocephaly and/or trigonocephaly. 9 In this study, to identify novel candidate genes for NDDs, we performed exome or targeted sequencing on DNAs of 558 Japanese NDD patients with a rather predominant focus on those associated with trigonocephaly, and identified rare de novo, hemizygous, homozygous, and compound heterozygous variants in genes including functionally related MSX2 and PJA1. Functional analyses of these variants in vitro and in vivo further supported that these are genes for NDDs.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders

Suzuki

Raveau

et al. 2020

Ann Clin Transl Neurol

Self Cite

View full text Add to dashboard Cite

Objective: Neurodevelopmental disorders (NDDs) often associate with epilepsy or craniofacial malformations. Recent large-scale DNA analyses identified hundreds of candidate genes for NDDs, but a large portion of the cases still remain unexplained. We aimed to identify novel candidate genes for NDDs. Methods: We performed exome sequencing of 95 patients with NDDs including 51 with trigonocephaly and subsequent targeted sequencing of additional 463 NDD patients, functional analyses of variant in vitro, and evaluations of autism spectrum disorder (ASD)-like phenotypes and seizure-related phenotypes in vivo. Results: We identified de novo truncation variants in nine novel genes; CYP1A1, C14orf119, FLI1, CYB5R4, SEL1L2, RAB11FIP2, ZMYND8, ZNF143, and MSX2. MSX2 variants have been described in patients with cranial malformations, and our present patient with the MSX2 de novo truncation variant showed cranial meningocele and partial epilepsy. MSX2 protein is known to be ubiquitinated by an E3 ubiquitin ligase PJA1, and interestingly we found a PJA1 hemizygous p.Arg376Cys variant recurrently in seven Japanese NDD patients; five with trigonocephaly and one with partial epilepsy, and the variant was absent in 886

show abstract

Naturally occurring splice variants dissect the functional domains of BHC80 and emphasize the need for RNA analysis

Hejla,

Huynh,

Samra

et al. 2024

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Pathogenic PHF21A variation causes PHF21A‐related neurodevelopmental disorders (NDDs). Although amorphic alleles, including haploinsufficiency, have been established as a disease mechanism, increasing evidence suggests that missense variants as well as frameshift variants extending the BHC80 carboxyl terminus also cause disease. Expanding on these, we report a proposita with intellectual disability and overgrowth and a novel de novo heterozygous PHF21A splice variant (NM_001352027.3:c.[153+1G>C];[=]) causing skipping of exon 6, which encodes an in‐frame BHC80 deletion (p.(Asn30_Gln51del)). This deletion disrupts a predicted leucine zipper domain and implicates this domain in BHC80 function and as a target of variation causing PHF21A‐related NDDs. This extension of understanding emphasizes the application of RNA analysis in precision genomic medicine practice.

show abstract

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

Cited by 16 publications

References 21 publications

Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism

Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism

A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders

Naturally occurring splice variants dissect the functional domains of BHC80 and emphasize the need for RNA analysis

Contact Info

Product

Resources

About