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Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly / M. WOODBURY-SMITH in Molecular Autism, 8 (2017)
[article]
Titre : Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly Type de document : Texte imprimé et/ou numérique Auteurs : M. WOODBURY-SMITH, Auteur ; E. DENEAULT, Auteur ; R. K. C. YUEN, Auteur ; S. WALKER, Auteur ; M. ZARREI, Auteur ; G. PELLECCHIA, Auteur ; J. L. HOWE, Auteur ; N. HOANG, Auteur ; M. UDDIN, Auteur ; C. R. MARSHALL, Auteur ; C. CHRYSLER, Auteur ; A. THOMPSON, Auteur ; P. SZATMARI, Auteur ; Stephen SCHERER, Auteur Article en page(s) : 59p. Langues : Anglais (eng) Mots-clés : Intellectual disability (ID) Rab39b RNAseq Whole genome sequencing (WGS) Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene RAB39B segregates with ASD phenotype. Methods: Clinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses. Results: Two males with an inherited RAB39B mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of RAB39B revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis. Conclusions: Penetrance for ASD is high among males but more variable among females with RAB39B mutations. A critical role for this gene in brain development and function is demonstrated. En ligne : http://dx.doi.org/10.1186/s13229-017-0175-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331
in Molecular Autism > 8 (2017) . - 59p.[article] Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly [Texte imprimé et/ou numérique] / M. WOODBURY-SMITH, Auteur ; E. DENEAULT, Auteur ; R. K. C. YUEN, Auteur ; S. WALKER, Auteur ; M. ZARREI, Auteur ; G. PELLECCHIA, Auteur ; J. L. HOWE, Auteur ; N. HOANG, Auteur ; M. UDDIN, Auteur ; C. R. MARSHALL, Auteur ; C. CHRYSLER, Auteur ; A. THOMPSON, Auteur ; P. SZATMARI, Auteur ; Stephen SCHERER, Auteur . - 59p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 59p.
Mots-clés : Intellectual disability (ID) Rab39b RNAseq Whole genome sequencing (WGS) Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene RAB39B segregates with ASD phenotype. Methods: Clinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses. Results: Two males with an inherited RAB39B mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of RAB39B revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis. Conclusions: Penetrance for ASD is high among males but more variable among females with RAB39B mutations. A critical role for this gene in brain development and function is demonstrated. En ligne : http://dx.doi.org/10.1186/s13229-017-0175-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 Outpatient visits and expenditures for children and adolescents diagnosed with autism spectrum disorders and co-occurring intellectual disability: An analysis of the national health insurance claims data / Lan-Ping LIN in Research in Autism Spectrum Disorders, 7-12 (December 2013)
[article]
Titre : Outpatient visits and expenditures for children and adolescents diagnosed with autism spectrum disorders and co-occurring intellectual disability: An analysis of the national health insurance claims data Type de document : Texte imprimé et/ou numérique Auteurs : Lan-Ping LIN, Auteur ; Chiung-Ying KUAN, Auteur ; Shang-Wei HSU, Auteur ; Tzong-Nan LEE, Auteur ; Chia-Im LAI, Auteur ; Jia-Lin WU, Auteur ; Jin-Ding LIN, Auteur Article en page(s) : p.1625-1630 Langues : Anglais (eng) Mots-clés : Autism spectrum disorders (ASD) Intellectual disability (ID) Medical expenditure Outpatient Healthcare Index. décimale : PER Périodiques Résumé : Abstract The primary healthcare service profile is important and provides valuable information on healthcare policies for patients with autism spectrum disorders (ASD) and co-occurring conditions. The present study analyzed data associated with outpatient care visits and expenditures in patients with ASD and co-occurring intellectual disability (ID) using healthcare setting insurance claims data in Taiwan. A retrospective analysis was conducted by merging database of healthcare setting medical care discharge claims used by the Taiwan Bureau of National Health Insurance and Disability Registration System. There were 5273 children and adolescents with ASD who utilized outpatient services during the year 2005. Taiwan NHI claims (510 cases with co-occurring ID and 4763 cases without ID) were analyzed in the study. The study found that ASD subjects without ID have 1.6-fold the annual outpatient visits of those with ID (13 visits vs. 8 visits). Those ASD cases with ID are more likely to use psychiatric visits and that individuals without ID use more rehabilitation services. The total annual outpatient care expenditure from 5273 children and adolescents with ASD was 137,842,159 New Taiwan Dollars (NTD). Cases without ID have increased medical costs compared with cases with ID in annual outpatient care expenditure (OR = 1.274, 95% CI = 1.173–1.384). A logistic regression analysis of outpatient expenditure (low vs. high) showed that of the cases with ASD and ID, the factors of age (reference: 6–11 years; 0–5 years, OR = 1.383, 95% CI = 1.106–1.730), severe illness (reference: no; OR = 1.838, 95% CI = 1.538–2.196), low income family (reference: no; OR = 1.799, 95% CI = 1.344–2.408), medical care setting (reference: clinic; private hospital: OR = 1.769, 95% CI = 1.199–2.610; corporate hospital, OR = 1.624, 95% CI = 1.139–2.315) and clinical unit (reference: psychiatric; rehabilitation, OR = 1.913, 95% CI = 1.651–2.344; pediatrics, OR = 1.461, 95% CI = 1.014–2.017) had more outpatient costs (on average) than their counterparts. Finally, this study highlights that health authorities should pay much attention to the factors which correlated to medical needs and costs of children and adolescents with ASD and ID to ensure efficacy of medication and continuing support for patients in treatment. En ligne : http://dx.doi.org/10.1016/j.rasd.2013.09.003 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=219
in Research in Autism Spectrum Disorders > 7-12 (December 2013) . - p.1625-1630[article] Outpatient visits and expenditures for children and adolescents diagnosed with autism spectrum disorders and co-occurring intellectual disability: An analysis of the national health insurance claims data [Texte imprimé et/ou numérique] / Lan-Ping LIN, Auteur ; Chiung-Ying KUAN, Auteur ; Shang-Wei HSU, Auteur ; Tzong-Nan LEE, Auteur ; Chia-Im LAI, Auteur ; Jia-Lin WU, Auteur ; Jin-Ding LIN, Auteur . - p.1625-1630.
Langues : Anglais (eng)
in Research in Autism Spectrum Disorders > 7-12 (December 2013) . - p.1625-1630
Mots-clés : Autism spectrum disorders (ASD) Intellectual disability (ID) Medical expenditure Outpatient Healthcare Index. décimale : PER Périodiques Résumé : Abstract The primary healthcare service profile is important and provides valuable information on healthcare policies for patients with autism spectrum disorders (ASD) and co-occurring conditions. The present study analyzed data associated with outpatient care visits and expenditures in patients with ASD and co-occurring intellectual disability (ID) using healthcare setting insurance claims data in Taiwan. A retrospective analysis was conducted by merging database of healthcare setting medical care discharge claims used by the Taiwan Bureau of National Health Insurance and Disability Registration System. There were 5273 children and adolescents with ASD who utilized outpatient services during the year 2005. Taiwan NHI claims (510 cases with co-occurring ID and 4763 cases without ID) were analyzed in the study. The study found that ASD subjects without ID have 1.6-fold the annual outpatient visits of those with ID (13 visits vs. 8 visits). Those ASD cases with ID are more likely to use psychiatric visits and that individuals without ID use more rehabilitation services. The total annual outpatient care expenditure from 5273 children and adolescents with ASD was 137,842,159 New Taiwan Dollars (NTD). Cases without ID have increased medical costs compared with cases with ID in annual outpatient care expenditure (OR = 1.274, 95% CI = 1.173–1.384). A logistic regression analysis of outpatient expenditure (low vs. high) showed that of the cases with ASD and ID, the factors of age (reference: 6–11 years; 0–5 years, OR = 1.383, 95% CI = 1.106–1.730), severe illness (reference: no; OR = 1.838, 95% CI = 1.538–2.196), low income family (reference: no; OR = 1.799, 95% CI = 1.344–2.408), medical care setting (reference: clinic; private hospital: OR = 1.769, 95% CI = 1.199–2.610; corporate hospital, OR = 1.624, 95% CI = 1.139–2.315) and clinical unit (reference: psychiatric; rehabilitation, OR = 1.913, 95% CI = 1.651–2.344; pediatrics, OR = 1.461, 95% CI = 1.014–2.017) had more outpatient costs (on average) than their counterparts. Finally, this study highlights that health authorities should pay much attention to the factors which correlated to medical needs and costs of children and adolescents with ASD and ID to ensure efficacy of medication and continuing support for patients in treatment. En ligne : http://dx.doi.org/10.1016/j.rasd.2013.09.003 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=219 The Social Communication Questionnaire for adults with intellectual disability: SCQ-AID / Olivia DERKS in Autism Research, 10-9 (September 2017)
[article]
Titre : The Social Communication Questionnaire for adults with intellectual disability: SCQ-AID Type de document : Texte imprimé et/ou numérique Auteurs : Olivia DERKS, Auteur ; Manuel HEINRICH, Auteur ; Whitney BROOKS, Auteur ; Paula STERKENBURG, Auteur ; Jane MCCARTHY, Auteur ; Lisa UNDERWOOD, Auteur ; Tanja SAPPOK, Auteur Article en page(s) : p.1481-1490 Langues : Anglais (eng) Mots-clés : autism spectrum disorder (ASD) intellectual disability (ID) social communication questionnaire (SCQ) assessment validity Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) frequently co-occurs with intellectual disability (ID) and often remains undiagnosed until adulthood. The Social Communication Questionnaire (SCQ) is a widely used measure to screen for ASD. To improve the utility of the SCQ for adults with ID, the aim of this study was to develop an ID-specific and adult appropriate algorithm for the SCQ using a core set of valid items. These items were identified in one sample (N = 226) and further cross-validated in a second, independent sample (N = 225) from Germany, England and the U.S. The newly developed algorithm has 24 items compared with the 40 items in the original instrument. The reduced item core set yielded similar diagnostic validity as the original algorithm with good sensitivity values (0.81–0.89) and low specificity values (0.62–0.72). Overall, these results suggest that the removed items may not carry diagnostically relevant information in adults with ID; thus, excluding these items may result in a more efficient and age-appropriate screening measure for this population. However, due to the low specificity values, a comprehensive assessment is essential for a final diagnostic assignment. En ligne : http://dx.doi.org/10.1002/aur.1795 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=320
in Autism Research > 10-9 (September 2017) . - p.1481-1490[article] The Social Communication Questionnaire for adults with intellectual disability: SCQ-AID [Texte imprimé et/ou numérique] / Olivia DERKS, Auteur ; Manuel HEINRICH, Auteur ; Whitney BROOKS, Auteur ; Paula STERKENBURG, Auteur ; Jane MCCARTHY, Auteur ; Lisa UNDERWOOD, Auteur ; Tanja SAPPOK, Auteur . - p.1481-1490.
Langues : Anglais (eng)
in Autism Research > 10-9 (September 2017) . - p.1481-1490
Mots-clés : autism spectrum disorder (ASD) intellectual disability (ID) social communication questionnaire (SCQ) assessment validity Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) frequently co-occurs with intellectual disability (ID) and often remains undiagnosed until adulthood. The Social Communication Questionnaire (SCQ) is a widely used measure to screen for ASD. To improve the utility of the SCQ for adults with ID, the aim of this study was to develop an ID-specific and adult appropriate algorithm for the SCQ using a core set of valid items. These items were identified in one sample (N = 226) and further cross-validated in a second, independent sample (N = 225) from Germany, England and the U.S. The newly developed algorithm has 24 items compared with the 40 items in the original instrument. The reduced item core set yielded similar diagnostic validity as the original algorithm with good sensitivity values (0.81–0.89) and low specificity values (0.62–0.72). Overall, these results suggest that the removed items may not carry diagnostically relevant information in adults with ID; thus, excluding these items may result in a more efficient and age-appropriate screening measure for this population. However, due to the low specificity values, a comprehensive assessment is essential for a final diagnostic assignment. En ligne : http://dx.doi.org/10.1002/aur.1795 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=320 The validity of the social communication questionnaire in adults with intellectual disability / Whitney T. BROOKS in Research in Autism Spectrum Disorders, 7-2 (February 2013)
[article]
Titre : The validity of the social communication questionnaire in adults with intellectual disability Type de document : Texte imprimé et/ou numérique Auteurs : Whitney T. BROOKS, Auteur ; Betsey A. BENSON, Auteur Année de publication : 2013 Article en page(s) : p.247-255 Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorders (ASD) Intellectual disability (ID) Adults Social Communication Questionnaire (SCQ) Screening measures Validity Index. décimale : PER Périodiques Résumé : This study assessed the validity of the Social Communication Questionnaire (SCQ) in a sample of 69 adults, aged 18'40 years old. Participants included 21 adults diagnosed with an autism spectrum disorder (ASD) and intellectual disability (ID), and 48 individuals diagnosed with ID and no diagnosis of an ASD. The SCQ yielded a sensitivity of .71 and a specificity of .77 at the authors' recommended cutoff score of 15 (Berument et al., 1999). However, when sensitivity was prioritized over specificity, the optimal cutoff score was 12, which yielded a sensitivity of .86 and a specificity of .60. The internal consistencies of the total scale (' = .87), the social interaction subscale (' = .83), and the restricted repetitive behavior subscale (' = .81) were good, but the communication subscale performed poorly (' = .48). The SCQ shows promise as a screening measure for adults with ID whose early developmental history may be unavailable. A lower cutoff score than the authors originally proposed is recommended in adults. En ligne : http://dx.doi.org/10.1016/j.rasd.2012.10.002 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=186
in Research in Autism Spectrum Disorders > 7-2 (February 2013) . - p.247-255[article] The validity of the social communication questionnaire in adults with intellectual disability [Texte imprimé et/ou numérique] / Whitney T. BROOKS, Auteur ; Betsey A. BENSON, Auteur . - 2013 . - p.247-255.
Langues : Anglais (eng)
in Research in Autism Spectrum Disorders > 7-2 (February 2013) . - p.247-255
Mots-clés : Autism Spectrum Disorders (ASD) Intellectual disability (ID) Adults Social Communication Questionnaire (SCQ) Screening measures Validity Index. décimale : PER Périodiques Résumé : This study assessed the validity of the Social Communication Questionnaire (SCQ) in a sample of 69 adults, aged 18'40 years old. Participants included 21 adults diagnosed with an autism spectrum disorder (ASD) and intellectual disability (ID), and 48 individuals diagnosed with ID and no diagnosis of an ASD. The SCQ yielded a sensitivity of .71 and a specificity of .77 at the authors' recommended cutoff score of 15 (Berument et al., 1999). However, when sensitivity was prioritized over specificity, the optimal cutoff score was 12, which yielded a sensitivity of .86 and a specificity of .60. The internal consistencies of the total scale (' = .87), the social interaction subscale (' = .83), and the restricted repetitive behavior subscale (' = .81) were good, but the communication subscale performed poorly (' = .48). The SCQ shows promise as a screening measure for adults with ID whose early developmental history may be unavailable. A lower cutoff score than the authors originally proposed is recommended in adults. En ligne : http://dx.doi.org/10.1016/j.rasd.2012.10.002 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=186 Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism / H. G. KIM in Molecular Autism, 10 (2019)
[article]
Titre : Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism Type de document : Texte imprimé et/ou numérique Auteurs : H. G. KIM, Auteur ; J. A. ROSENFELD, Auteur ; D. A. SCOTT, Auteur ; G. BENEDICTE, Auteur ; J. D. LABONNE, Auteur ; J. BROWN, Auteur ; M. MCGUIRE, Auteur ; S. MAHIDA, Auteur ; S. NAIDU, Auteur ; J. GUTIERREZ, Auteur ; G. LESCA, Auteur ; V. DES PORTES, Auteur ; A. L. BRUEL, Auteur ; A. SORLIN, Auteur ; F. XIA, Auteur ; Y. CAPRI, Auteur ; E. MULLER, Auteur ; D. MCKNIGHT, Auteur ; E. TORTI, Auteur ; F. RUSCHENDORF, Auteur ; O. HUMMEL, Auteur ; Z. ISLAM, Auteur ; P. R. KOLATKAR, Auteur ; L. C. LAYMAN, Auteur ; D. RYU, Auteur ; I. K. KONG, Auteur ; S. MADAN-KHETARPAL, Auteur ; C. H. KIM, Auteur Article en page(s) : 35 p. Langues : Anglais (eng) Mots-clés : AT Hook domain Autism spectrum disorder (ASD) Bhc80 Intellectual disability (ID) Intrinsically disordered region (IDR) Kdm1a Neurodevelopmental disorders Phf21a Potocki-Shaffer syndrome (PSS) Index. décimale : PER Périodiques Résumé : Background: PHF21A 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. Methods: Diagnostic 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. Results: We 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. Conclusion: Deleterious 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. En ligne : https://dx.doi.org/10.1186/s13229-019-0286-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=408
in Molecular Autism > 10 (2019) . - 35 p.[article] Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism [Texte imprimé et/ou numérique] / H. G. KIM, Auteur ; J. A. ROSENFELD, Auteur ; D. A. SCOTT, Auteur ; G. BENEDICTE, Auteur ; J. D. LABONNE, Auteur ; J. BROWN, Auteur ; M. MCGUIRE, Auteur ; S. MAHIDA, Auteur ; S. NAIDU, Auteur ; J. GUTIERREZ, Auteur ; G. LESCA, Auteur ; V. DES PORTES, Auteur ; A. L. BRUEL, Auteur ; A. SORLIN, Auteur ; F. XIA, Auteur ; Y. CAPRI, Auteur ; E. MULLER, Auteur ; D. MCKNIGHT, Auteur ; E. TORTI, Auteur ; F. RUSCHENDORF, Auteur ; O. HUMMEL, Auteur ; Z. ISLAM, Auteur ; P. R. KOLATKAR, Auteur ; L. C. LAYMAN, Auteur ; D. RYU, Auteur ; I. K. KONG, Auteur ; S. MADAN-KHETARPAL, Auteur ; C. H. KIM, Auteur . - 35 p.
Langues : Anglais (eng)
in Molecular Autism > 10 (2019) . - 35 p.
Mots-clés : AT Hook domain Autism spectrum disorder (ASD) Bhc80 Intellectual disability (ID) Intrinsically disordered region (IDR) Kdm1a Neurodevelopmental disorders Phf21a Potocki-Shaffer syndrome (PSS) Index. décimale : PER Périodiques Résumé : Background: PHF21A 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. Methods: Diagnostic 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. Results: We 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. Conclusion: Deleterious 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. En ligne : https://dx.doi.org/10.1186/s13229-019-0286-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=408 Neurogenetic analysis of childhood disintegrative disorder / A. R. GUPTA in Molecular Autism, 8 (2017)
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