Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability
De Hayr L, Blok LER, Dias KR, Long J, Begemann A, Moir RD, Willis IM, Mocera M, Siegel G, Steindl K, Evans CA, Zhu Y, Zhang F, Field M, Ma A, Adès L, Josephi-Taylor S, Pfundt R, Zaki MS, Tomoum H, Gregor A, Laube J, Reis A, Maddirevula S, Hashem MO, Zweier M, Alkuraya FS, Maroofian R, Buckley MF, Gleeson JG, Zweier C, Coll-Tané M, Koolen DA, Rauch A, Roscioli T, Schenck A, Harvey RJ. Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability. Genet Med. 2024 Nov 7
Genet Med. 2024 Nov 7:101253. doi: 10.1016/j.gim.2024.101253. Online ahead of print.
ABSTRACT
PURPOSE: This study details a novel syndromic form of autosomal recessive intellectual disability resulting from recessive variants in GTF3C3, encoding a key component of the DNA-binding transcription factor IIIC, which has a conserved role in RNA polymerase III-mediated transcription.
METHODS: Exome sequencing, minigene analysis, molecular modeling, RNA polymerase III reporter gene assays, and Drosophila knockdown models were utilized to characterize GTF3C3 variants.
RESULTS: Twelve affected individuals from 7 unrelated families were identified with homozygous or compound heterozygous missense variants in GTF3C3 including c.503C>T p.(Ala168Val), c.1268T>C p.(Leu423Pro), c.1436A>G p.(Tyr479Cys), c.2419C>T p.(Arg807Cys), and c.2420G>A p.(Arg807His). The cohort presented with intellectual disability, variable nonfamilial facial features, motor impairments, seizures, and cerebellar/corpus callosum malformations. Consistent with disruptions in intra- and intermolecular interactions observed in molecular modeling, RNA polymerase III reporter assays confirmed that the majority of missense variants resulted in a loss of function. Minigene analysis of the recurrent c.503C>T p.(Ala168Val) variant confirmed the introduction of a cryptic donor site into exon 4, resulting in mRNA missplicing. Consistent with the clinical features of this cohort, neuronal loss of Gtf3c3 in Drosophila induced seizure-like behavior, motor impairment, and learning deficits.
CONCLUSION: These findings confirm that GTF3C3 variants result in an autosomal recessive form of syndromic intellectual disability.
PMID:
39636576 | DOI:
10.1016/j.gim.2024.101253
November 7, 2024
Genetic Neurologic Disease
Early Newborn Metabolic Patterning and Sudden Infant Death Syndrome
Oltman SP, Rogers EE, Baer RJ, Amsalu R, Bandoli G, Chambers CD, Cho H, Dagle JM, Karvonen KL, Kingsmore SF, McKenzie-Sampson S, Momany A, Ontiveros E, Protopsaltis LD, Rand L, Kobayashi ES, Steurer MA, Ryckman KK, Jelliffe-Pawlowski LL. Early Newborn Metabolic Patterning and Sudden Infant Death Syndrome. JAMA Pediatr. 2024 Nov 1
Abstract
Importance: Sudden infant death syndrome (SIDS) is a major cause of infant death in the US. Previous research suggests that inborn errors of metabolism may contribute to SIDS, yet the relationship between SIDS and biomarkers of metabolism remains unclear.
Objective: To evaluate and model the association between routinely measured newborn metabolic markers and SIDS in combination with established risk factors for SIDS.
Design, setting, and participants: This was a case-control study nested within a retrospective cohort using data from the California Office of Statewide Health Planning and Development and the California Department of Public Health. The study population included infants born in California between 2005 and 2011 with full metabolic data collected as part of routine newborn screening (NBS). SIDS cases were matched to controls at a ratio of 1:4 by gestational age and birth weight z score. Matched data were split into training (2/3) and testing (1/3) subsets. Data were analyzed from January 2005 to December 2011.
Exposures: Metabolites measured by NBS and established risk factors for SIDS.
Main outcomes and measures: The primary outcome was SIDS. Logistic regression was used to evaluate the association between metabolic markers combined with known risk factors and SIDS.
Results: Of 2 276 578 eligible infants, 354 SIDS (0.016%) cases (mean [SD] gestational age, 38.3 [2.3] weeks; 220 male [62.1%]) and 1416 controls (mean [SD] gestational age, 38.3 [2.3] weeks; 723 male [51.1%]) were identified. In multivariable analysis, 14 NBS metabolites were significantly associated with SIDS in a univariate analysis: 17-hydroxyprogesterone, alanine, methionine, proline, tyrosine, valine, free carnitine, acetyl-L-carnitine, malonyl carnitine, glutarylcarnitine, lauroyl-L-carnitine, dodecenoylcarnitine, 3-hydroxytetradecanoylcarnitine, and linoleoylcarnitine. The area under the receiver operating characteristic curve for a 14-marker SIDS model, which included 8 metabolites, was 0.75 (95% CI, 0.72-0.79) in the training set and was 0.70 (95% CI, 0.65-0.76) in the test set. Of 32 infants in the test set with model-predicted probability greater than 0.5, a total of 20 (62.5%) had SIDS. These infants had 14.4 times the odds (95% CI, 6.0-34.5) of having SIDS compared with those with a model-predicted probability less than 0.1.
Conclusions and relevance: Results from this case-control study showed an association between aberrant metabolic analytes at birth and SIDS. These findings suggest that we may be able to identify infants at increased risk for SIDS soon after birth, which could inform further mechanistic research and clinical efforts focused on monitoring and prevention.
PMID: 39250160 | DOI: 10.1001/jamapediatrics.2024.3033
November 1, 2024
Infant Mortality
Treating the Untreatable: Antisense Oligonucleotides as an Individualized Therapy for Rare Genetic Kidney Disease
Tekendo-Ngongang C, Gleeson JG, Mignon L. Treating the Untreatable: Antisense Oligonucleotides as an Individualized Therapy for Rare Genetic Kidney Diseases. J Am Soc Nephrol. 2024 Dec 1
October 30, 2024
The Face and Features of RNU4-2: A New, Common, Recognizable, Yet Hidden Neurodevelopmental Disorder
Barbour K, Bainbridge MN, Wigby K, Besterman AD, Chuang NA, Tobin LE, Del Campo M, Lenberg J, Bird LM, Friedman J. The Face and Features of RNU4-2: A New, Common, Recognizable, Yet Hidden Neurodevelopmental Disorder. Pediatr Neurol. 2024 Sep 21;161:188-193. doi: 10.1016/j.pediatrneurol.2024.09.015
Pediatr Neurol. 2024 Sep 21;161:188-193. doi: 10.1016/j.pediatrneurol.2024.09.015. Online ahead of print.
ABSTRACT
BACKGROUND: RNU4-2 is a newly identified, noncoding gene responsible for a significant proportion of individuals with neurodevelopmental disorders (NDDs). Diagnosis is hampered by the inability of commonly employed clinical testing methods, including exome sequencing and currently formulated multigene panels, to detect variants in the noncoding region. The relatively high prevalence of this condition, predicted to affect thousands of undiagnosed children with NDDs, makes it even more relevant to have better tools to facilitate diagnosis. The initial report of the gene-disease association outlined aggregate phenotypic features but lacked detailed patient evaluations, potentially under-reporting phenotypic features and failing to highlight unique aspects. We aimed to identify individuals with RNU4-2 gene variants to deeply phenotype the clinical profile. We sought to define key features that may suggest the diagnosis, to highlight individuals for whom specialized testing, able to detect noncoding region variants, may be indicated.
METHODS: We reviewed genomic data from 6,734 individuals, identifying five with recurrent de novo RNU4-2 (n.64_65insT) variants. We clinically evaluated four. Findings were compared with those previously reported.
RESULTS: We identify common clinical features, a distinctive dysmorphic facial pattern, and shared imaging abnormalities. We describe novel aspects including longitudinal trajectory and treatment response.
CONCLUSIONS: Enhanced recognition of the RNU4-2 (n.64_65insT-common variant) phenotype, particularly the dysmorphic facial features, will facilitate earlier diagnosis. Distinctive characteristics will guide the selection of patients for testing able to detect RNU4-2 variants: genome sequencing or targeted gene testing. Furthermore, health and research systems may identify undiagnosed patients by querying databases for individuals exhibiting the traits described herein.
PMID:
39423747 | DOI:
10.1016/j.pediatrneurol.2024.09.015
October 30, 2024
Neurogenomics
Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay
Tan S, Zhang Q, Zhan R, Luo S, Han Y, Yu B, Muss C, Pingault V, Marlin S, Delahaye A, Peters S, Perne C, Kreiß M, Spataro N, Trujillo-Quintero JP, Racine C, Tran-Mau-Them F, Phornphutkul C, Besterman AD, Martinez J, Wang X, Tian X, Srivastava S, Urion DK, Madden JA, Saif HA, Morrow MM, Begtrup A, Li X, Jurgensmeyer S, Leahy P, Zhou S, Li F, Hu Z, Tan J, Xia K, Guo H. Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay. Mol Psychiatry. 2024 Oct 29
Mol Psychiatry. 2024 Oct 29. doi: 10.1038/s41380-024-02806-z. Online ahead of print.
ABSTRACT
De novo variants adjacent to the canonical splicing sites or in the well-defined splicing-related regions are more likely to impair splicing but remain under-investigated in autism spectrum disorder (ASD). By analyzing large, recent ASD genome sequencing cohorts, we find a significant burden of de novo potential splicing-disrupting variants (PSDVs) in 5048 probands compared to 4090 unaffected siblings. We identified 55 genes with recurrent de novo PSDVs that were highly intolerant to variation. Forty-six of these genes have not been strongly implicated in ASD or other neurodevelopmental disorders previously, including GSK3B. Through international, multicenter collaborations, we assembled genotype and phenotype data for 15 individuals with GSK3B variants and identified common phenotypes including developmental delay, ASD, sleeping disturbance, and aggressive behavior. Using available single-cell transcriptomic data, we show that GSK3B is enriched in dorsal progenitors and intermediate forms of excitatory neurons in the developing brain. We showed that Gsk3b knockdown in mouse excitatory neurons interferes with dendrite arborization and spine maturation which could not be rescued by de novo missense variants identified from affected individuals. In summary, our findings suggest that PSDVs may play an important role in the genetic etiology of ASD and allow for the prioritization of new ASD candidate genes. Importantly, we show that genetic variation resulting in GSK3B loss-of-function can lead to a neurodevelopmental disorder with core features of ASD and developmental delay.
PMID:
39472663 | DOI:
10.1038/s41380-024-02806-z
October 29, 2024
Genetic Neurologic Disease
Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations
Nagy S, Pagnamenta AT, Cali E, Braakman HMH, Wijntjes J, Kusters B, Gotkine M, Elpeleg O, Meiner V, Lenberg J, Wigby K, Friedman J, Perry LD, Rossor AM, Uhrova Meszarosova A, Thomasova D, Jacob S, O’Driscoll M, De Simone L, Grange DK, Sommerville R, Firoozfar Z, Alavi S, Mazaheri M, Parmar JM, Lamont PJ, Pini V, Sarkozy A, Muntoni F, Ravenscroft G, Jones E, O’Rourke D, Nel M, Heckmann JM, Kvalsund M, Kapapa MM, Wa Somwe S, Bearden DR, Çakar A, Childs AM, Horvath R, Reilly MM, Houlden H, Maroofian R. Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations. Brain Commun. 2024 Oct 28
Brain Commun. 2024 Oct 28;6(6):fcae377. doi: 10.1093/braincomms/fcae377. eCollection 2024.
ABSTRACT
A newly identified subtype of hereditary axonal motor neuropathy, characterized by early proximal limb involvement, has been discovered in a cohort of 34 individuals with biallelic variants in von Willebrand factor A domain-containing 1 (VWA1). This study further delineates the disease characteristics in a cohort of 20 individuals diagnosed through genome or exome sequencing, incorporating neurophysiological, laboratory and imaging data, along with data from previously reported cases across three different studies. Newly reported clinical features include hypermobility/hyperlaxity, axial weakness, dysmorphic signs, asymmetric presentation, dystonic features and, notably, upper motor neuron signs. Foot drop, foot deformities and distal leg weakness followed by early proximal leg weakness are confirmed to be initial manifestations. Additionally, this study identified 11 novel VWA1 variants, reaffirming the 10 bp insertion-induced p.Gly25ArgfsTer74 as the most prevalent disease-causing allele, with a carrier frequency of ∼1 in 441 in the UK and Western European population. Importantly, VWA1-related pathology may mimic various neuromuscular conditions, advocating for its inclusion in diverse gene panels spanning hereditary neuropathies to muscular dystrophies. The study highlights the potential of lower quality control filters in exome analysis to enhance diagnostic yield of VWA1 disease that may account for up to 1% of unexplained hereditary neuropathies.
PMID:
39502942 | PMC:
PMC11535570 | DOI:
10.1093/braincomms/fcae377
October 28, 2024
Neurogenomics
Clinical factors associated with genetic diagnosis in suspected neurogenetic disorders in a tertiary care clinic
Wong NR, Klomhaus A, Adams DJ, Schneider BN, Mehta S, DiStefano C, Wilson RB, Martinez-Agosto JA, Jeste SS, Besterman AD. Clinical factors associated with genetic diagnosis in suspected neurogenetic disorders in a tertiary care clinic. Genet Med. 2024 Oct 10
Genet Med. 2024 Oct 10:101252. doi: 10.1016/j.gim.2024.101252. Online ahead of print.
ABSTRACT
PURPOSE: This study aimed to identify phenotypic factors associated with genetic diagnoses in patients with neurodevelopmental disorders and generate a decision tree to assist clinicians in identifying patients most likely to receive a positive result on genetic testing.
METHODS: We retrospectively reviewed the charts of 316 patients evaluated in a neurodevelopmental clinic between 2014 and 2019. Patients were categorized based on genetic test results. Analyses were performed to identify variables that discriminate between patients with and without a genetic diagnosis.
RESULTS: Patients with a genetic diagnosis were more likely to be female and have a history of motor delay, hypotonia, congenital heart disease, and early intervention. Classification and regression tree analysis revealed that 75% of patients with motor delay had a genetic diagnosis. In patients without motor delay, hypotonia, age of walking, and age at initial evaluation were important indicators of a genetic diagnosis.
CONCLUSION: Our findings suggest that motor delay and hypotonia are associated with genetic diagnoses in children with neurodevelopmental disorders. The decision tree highlights patient subsets at greater risk and suggests possible phenotypic screens. Future studies could develop validated decision trees based on phenotypic data to assist clinicians in stratifying patients for genetic testing.
PMID:
39395029 | DOI:
10.1016/j.gim.2024.101252
October 10, 2024
Genetic Neurologic DiseaseNeurogenomics
Clinical and Molecular Profiles of a Cohort of Egyptian Patients with Collagen VI-Related Dystrophy
Sharaf-Eldin WE, Rafat K, Issa MY, Elbendary HM, Eissa NR, Hawaary B, Gaboon NEA, Maroofian R, Gleeson JG, Essawi ML, Zaki MS. Clinical and Molecular Profiles of a Cohort of Egyptian Patients with Collagen VI-Related Dystrophy. J Mol Neurosci. 2024 Oct 5
J Mol Neurosci. 2024 Oct 5;74(4):93. doi: 10.1007/s12031-024-02266-8.
ABSTRACT
Collagen VI-related dystrophies (COL6-RD) display a wide spectrum of disease severity and genetic variability ranging from mild Bethlem myopathy (BM) to severe Ullrich congenital muscular dystrophy (UCMD) and the intermediate severities in between with dual modes of inheritance, dominant and recessive. In the current study, next-generation sequencing demonstrated potential variants in the genes coding for the three alpha chains of collagen VI (COL6A1, COL6A2, or COL6A3) in a cohort of Egyptian patients with progressive muscle weakness (n = 23). Based on the age of disease onset and the patient clinical course, subjects were diagnosed as follows: 12 with UCMD, 8 with BM, and 3 with intermediate disease form. Fourteen pathogenic variants, including 5 novel alterations, were reported in the enrolled subjects. They included 3 missense, 3 frameshift, and 6 splicing variants in 4, 3, and 6 families, respectively. In addition, a nonsense variant in a single family and an inframe variant in 3 different families were also detected. Recessive and dominant modes of inheritance were recorded in 9 and 8 families, respectively. According to ACMG guidelines, variants were classified as pathogenic (n = 7), likely pathogenic (n = 4), or VUS (n = 3) with significant pathogenic potential. To our knowledge, the study provided the first report of the clinical and genetic findings of a cohort of Egyptian patients with collagen VI deficiency. Inter- and intra-familial clinical variability was evident among the study cohort.
PMID:
39367186 | DOI:
10.1007/s12031-024-02266-8
October 5, 2024
Genetic Neurologic Disease
Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder
Rawlins LE, Maroofian R, Cannon SJ, Daana M, Zamani M, Ghani S, Leslie JS, Ubeyratna N, Khan N, Khan H, Scardamaglia A, Cloarec R, Khan SA, Umair M, Sadeghian S, Galehdari H, Al-Maawali A, Al-Kindi A, Azizimalamiri R, Shariati G, Ahmad F, Al-Futaisi A, Rodriguez Cruz PM, Salazar-Villacorta A, Ndiaye M, Diop AG, Sedaghat A, Saberi A, Hamid M, Zaki MS, Vona B, Owrang D, Alhashem AM, Obeid M, Khan A, Beydoun A, Najjar M, Tajsharghi H, Zifarelli G, Bauer P, Hakami WS, Hashem AMA, Boustany RN, Burglen L, Alavi S, Gunning AC, Owens M, Karimiani EG, Gleeson JG, Milh M, Salah S, Khan J, Haucke V, Wright CF, McGavin L, Elpeleg O, Shabbir MI, Houlden H, Ebner M, Baple EL, Crosby AH. Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder. Genet Med. 2024 Sep 20
Genet Med. 2024 Sep 20:101278. doi: 10.1016/j.gim.2024.101278. Online ahead of print.
ABSTRACT
PURPOSE: Biallelic INPP4A variants have recently been associated with severe neurodevelopmental disease in single case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations.
METHODS: Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies.
RESULTS: We characterize a clinically variable disorder with cardinal features including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in Inpp4a-/- mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition.
CONCLUSION: Our studies comprehensively characterise INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.
PMID:
39315527 | DOI:
10.1016/j.gim.2024.101278
September 20, 2024
Neurogenomics
Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders
Cali E, Quirin T, Rocca C, Efthymiou S, Riva A, Marafi D, Zaki MS, Suri M, Dominguez R, Elbendary HM, Alavi S, Abdel-Hamid MS, Morsy H, Mau-Them FT, Nizon M, Tesner P, Ryba L, Zafar F, Rana N, Saadi NW, Firoozfar Z, Gencpinar P, Unay B, Ustun C, Bruel AL, Coubes C, Stefanich J, Sezer O, Agolini E, Novelli A, Vasco G, Lettori D, Milh M, Villard L, Zeidler S, Opperman H, Strehlow V, Issa MY, El Khassab H, Chand P, Ibrahim S, Nejad-Rashidi A, Miryounesi M, Larki P, Morrison J, Cristian I, Thiffault I, Bertsch NL, Noh GJ, Pappas J, Moran E, Marinakis NM, Traeger-Synodinos J, Hosseini S, Abbaszadegan MR, Caumes R, Vissers LELM, Neshatdoust M, Montazer MZ, El Fahime E, Canavati C, Kamal L, Kanaan M, Askander O, Voinova V, Levchenko O, Haider S, Halbach SS, Maia ER, Mansoor S, Vivek J, Tawde S, Santhosh R Challa V, Gowda VK, Srinivasan VM, Victor LA, Pinero-Banos B, Hague J, Ei-Awady HA, Maria de Miranda Henriques-Souza A, Cheema HA, Anjum MN, Idkaidak S, Alqarajeh F, Atawneh O, Mor-Shaked H, Harel T, Zifarelli G, Bauer P, Kok F, Kitajima JP, Monteiro F, Josahkian J, Lesca G, Chatron N, Ville D, Murphy D, Neul JL, Mullegama SV, Begtrup A, Herman I, Mitani T, Posey JE, Tay CG, Javed I, Carr L, Kanani F, Beecroft F, Hane L, Abdelkreem E, Macek M, Bispo L, Elmaksoud MA, Hashemi-Gorji F, Pehlivan D, Amor DJ, Jamra RA, Chung WK, Ghayoor EK, Campeau P, Alkuraya FS, Pagnamenta AT, Gleeson J, Lupski JR, Striano P, Moreno-De-Luca A, Lafontaine DLJ, Houlden H, Maroofian R. Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders. Genet Med. 2024 Sep 10
Genet Med. 2024 Sep 10:101251. doi: 10.1016/j.gim.2024.101251. Online ahead of print.
ABSTRACT
PURPOSE: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear.
METHODS: We identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis.
RESULTS: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular in pre-rRNA processing.
CONCLUSION: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of ‘ribosomopathies’.
PMID:
39275948 | DOI:
10.1016/j.gim.2024.101251
September 10, 2024
Genetic Neurologic Disease
