11 research outputs found
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Functional Analysis of a Novel Potassium Channel (KCNA1) Mutation in Hereditary Mokymia
Myokymia is characterized by spontaneous, involuntary muscle fiber group contraction visible as vermiform movement of the overlying skin. Myokymia with episodic ataxia is a rare, autosomal dominant trait caused by mutations in KCNA1, encoding a voltage-gated potassium channel. In the present study, we report a family with four members affected with myokymia. Additional clinical features included motor delay initially diagnosed as cerebral palsy, worsening with febrile illness, persistent extensor plantar reflex, and absence of epilepsy or episodic ataxia. Mutation analysis revealed a novel c.676C>A substitution in the potassium channel gene KCNA1, resulting in a T226K nonconservative missense mutation in the Kv1.1 subunit in all affected individuals. Electrophysiological studies of the mutant channel expressed in Xenopus oocytes indicated a loss of function. Co-expression of WT and mutant cRNAs significantly reduced whole-oocyte current compared to expression of WT Kv1.1 alone
Cornelia de Lange syndrome in diverse populations
Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes—NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.Supplementary Table 1 Participants with photographs in Figures 2-5 from 10 countries.
Supplementary Table 2. Geometric and texture feature comparison of Global (combined African descent, Asian, Latin American, Caucasian) CdLS individuals with normal controls using digital facial analysis technology. The ranges of the geometric linear features were normalized by the ear‐to‐ear distance. Geometric angle features are presented in degrees. Texture features were computed at three scales (r1, r2, and r3). Features are presented in order of their relevance for the diagnosis of CdLS.
Supplementary Table 3. Geometric and texture feature comparison of African descent CdLS individuals with normal controls using digital facial analysis technology. The ranges of the geometric linear features were normalized by the ear‐to‐ear distance. Geometric angle features are presented in degrees. Texture features were computed at three scales (r1, r2, and r3). Features are presented in order of their relevance for the diagnosis of CdLS.
Supplementary Table 4. Geometric and texture feature comparison of Asian CdLS individuals with normal controls using digital facial analysis technology. The ranges of the geometric linear features were normalized by the ear‐to‐ear distance. Geometric angle features are presented in degrees. Texture features were computed at three scales (r1, r2, and r3). Features are presented in order of their relevance for the diagnosis of CdLS.
Supplementary Table 5. Geometric and texture feature comparison of Latin American CdLS individuals with normal controls using digital facial analysis technology. The ranges of the geometric linear features were normalized by the ear‐to‐ear distance. Geometric angle features are presented in degrees. Texture features were computed at three scales (r1, r2, and r3). Features are presented in order of their relevance for the diagnosis of CdLS.
Supplementary Table 6. Geometric and texture feature comparison of Caucasian CdLS individuals with normal controls using digital facial analysis technology. The ranges of the geometric linear features were normalized by the ear‐to‐ear distance. Geometric angle features are presented in degrees. Texture features were computed at three scales (r1, r2, and r3). Features are presented in order of their relevance for the diagnosis of CdLS.
Supplementary Figure 1. Global: Graph of area under the ROC curve (AUC), accuracy, sensitivity, and specificity versus the number of features selected.
Supplementary Figure 2. African: Graph of area under the ROC curve (AUC), accuracy, sensitivity, and specificity versus the number of features selected.
Supplementary Figure 3. Asian: Graph of area under the ROC curve (AUC), accuracy, sensitivity, and specificity versus the number of features selected.
Supplementary Figure 4. Latin American: Graph of area under the ROC curve (AUC), accuracy, sensitivity, and specificity versus the number of features selected.
Supplementary Figure 5. Caucasian: Graph of area under the ROC curve (AUC), accuracy, sensitivity, and specificity versus the number of features selectedPK and MM are supported by the Division of Intramural Research at the National Human Genome Research, NIH. Partial funding of this project was from a philanthropic gift from the Government of Abu Dhabi to the Children's National Health System. VS is supported by the Chulalongkorn Academic Advancement Into Its 2nd Century Project and the Thailand Research Fund. We would also like to acknowledge other clinicians who supported this work—MZ, JP, and GC. We would like to acknowledge that IDK, LD, MK, and SR are supported by the CdLS Center Endowed Funds at The Children's Hospital of Philadelphia and PO1 HD052860 from the NICHD. ES is supported by a fellowship from PKS Italia and PKSKids USA. LD was also supported by a postdoctoral training grant (T32 GM008638) from the NIGMS.http://wileyonlinelibrary.com/journal/ajmga2020-02-01hj2019Genetic
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Cornelia de Lange syndrome in diverse populations.
Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide
Cornelia de Lange Syndrome in Diverse Populations.
Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes—NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.Supplementary Table 1 Participants with photographs in Figures 2-5 from 10 countries.
Supplementary Table 2. Geometric and texture feature comparison of Global (combined African descent, Asian, Latin American, Caucasian) CdLS individuals with normal controls using digital facial analysis technology. The ranges of the geometric linear features were normalized by the ear‐to‐ear distance. Geometric angle features are presented in degrees. Texture features were computed at three scales (r1, r2, and r3). Features are presented in order of their relevance for the diagnosis of CdLS.
Supplementary Table 3. Geometric and texture feature comparison of African descent CdLS individuals with normal controls using digital facial analysis technology. The ranges of the geometric linear features were normalized by the ear‐to‐ear distance. Geometric angle features are presented in degrees. Texture features were computed at three scales (r1, r2, and r3). Features are presented in order of their relevance for the diagnosis of CdLS.
Supplementary Table 4. Geometric and texture feature comparison of Asian CdLS individuals with normal controls using digital facial analysis technology. The ranges of the geometric linear features were normalized by the ear‐to‐ear distance. Geometric angle features are presented in degrees. Texture features were computed at three scales (r1, r2, and r3). Features are presented in order of their relevance for the diagnosis of CdLS.
Supplementary Table 5. Geometric and texture feature comparison of Latin American CdLS individuals with normal controls using digital facial analysis technology. The ranges of the geometric linear features were normalized by the ear‐to‐ear distance. Geometric angle features are presented in degrees. Texture features were computed at three scales (r1, r2, and r3). Features are presented in order of their relevance for the diagnosis of CdLS.
Supplementary Table 6. Geometric and texture feature comparison of Caucasian CdLS individuals with normal controls using digital facial analysis technology. The ranges of the geometric linear features were normalized by the ear‐to‐ear distance. Geometric angle features are presented in degrees. Texture features were computed at three scales (r1, r2, and r3). Features are presented in order of their relevance for the diagnosis of CdLS.
Supplementary Figure 1. Global: Graph of area under the ROC curve (AUC), accuracy, sensitivity, and specificity versus the number of features selected.
Supplementary Figure 2. African: Graph of area under the ROC curve (AUC), accuracy, sensitivity, and specificity versus the number of features selected.
Supplementary Figure 3. Asian: Graph of area under the ROC curve (AUC), accuracy, sensitivity, and specificity versus the number of features selected.
Supplementary Figure 4. Latin American: Graph of area under the ROC curve (AUC), accuracy, sensitivity, and specificity versus the number of features selected.
Supplementary Figure 5. Caucasian: Graph of area under the ROC curve (AUC), accuracy, sensitivity, and specificity versus the number of features selectedPK and MM are supported by the Division of Intramural Research at the National Human Genome Research, NIH. Partial funding of this project was from a philanthropic gift from the Government of Abu Dhabi to the Children's National Health System. VS is supported by the Chulalongkorn Academic Advancement Into Its 2nd Century Project and the Thailand Research Fund. We would also like to acknowledge other clinicians who supported this work—MZ, JP, and GC. We would like to acknowledge that IDK, LD, MK, and SR are supported by the CdLS Center Endowed Funds at The Children's Hospital of Philadelphia and PO1 HD052860 from the NICHD. ES is supported by a fellowship from PKS Italia and PKSKids USA. LD was also supported by a postdoctoral training grant (T32 GM008638) from the NIGMS.http://wileyonlinelibrary.com/journal/ajmga2020-02-01hj2019Genetic
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Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy
Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)–associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype.
This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy.
All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family.
Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings
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HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder
Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders.
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We identified genetic variants of HNRNPC in 13 individuals with intellectual disability and global developmental delay. Through a meta-analysis of multiple cell types, we found that loss of HNRNPC affects alternative splicing, in particular of intellectual disability-associated genes. In vivo assays confirmed that neurodevelopment was affected by aberrant HNRNPC levels
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Dominant negative variants in IKZF2 cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay
BackgroundHelios (encoded by IKZF2), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and immune function. Although predominantly recognised for its role in the development and function of T lymphocytes, particularly the CD4+ regulatory T cells (Tregs), the expression and function of Helios extends beyond the immune system. During embryogenesis, Helios is expressed in a wide range of tissues, making genetic variants that disrupt the function of Helios strong candidates for causing widespread immune-related and developmental abnormalities in humans.MethodsWe performed detailed phenotypic, genomic and functional investigations on two unrelated individuals with a phenotype of immune dysregulation combined with syndromic features including craniofacial differences, sensorineural hearing loss and congenital abnormalities.ResultsGenome sequencing revealed de novo heterozygous variants that alter the critical DNA-binding zinc fingers (ZFs) of Helios. Proband 1 had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios (p.Gly136_Ser191dup) and Proband 2 had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios (p.Gly153Arg). Functional studies confirmed that both these variant proteins are expressed and that they interfere with the ability of the wild-type Helios protein to perform its canonical function—repressing IL2 transcription activity—in a dominant negative manner.ConclusionThis study is the first to describe dominant negative IKZF2 variants. These variants cause a novel genetic syndrome characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay
Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder
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Correction: Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations
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De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling
Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups from the inositol head group. PIs control membrane composition and play key roles in many cellular processes including actin dynamics, endosomal trafficking, autophagy, and nuclear functions. Mutations in phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] phosphatases cause a broad spectrum of neurodevelopmental disorders such as Lowe and Joubert syndromes and congenital muscular dystrophy with cataracts and intellectual disability, which are thus associated with increased levels of PI(4,5)P2. Here, we describe a neurodevelopmental disorder associated with an increase in the production of PI(4,5)P2 and with PI-signaling dysfunction. We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking. In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants.
We describe a neurodevelopmental disorder associated with de novo gain-of-function variants in PIP5KIγ kinase. The variants cause perturbed endosomal function resulting from increased production of phosphatidylinositol 4,5 bisphosphate and enhanced association of F-actin at endosomes. Moreover, mutant zebrafish larvae recapitulate the phenotypes observed in affected individuals from our cohort