Scientific Publications

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Duis blandit elit metus, mattis consectetur eros fermentum id. Cras lorem purus, finibus vel aliquam ac, porta in libero. Cras lorem purus, finibus vel aliquam ac, porta in libero.

  • Results Per Page

192 Results


Genotype-Phenotype Comparison in POGZ-Related Neurodevelopmental Disorders by Using Clinical Scoring

Nagy D, Verheyen S, Wigby KM, Borovikov A, Sharkov A, Slegesky V, Larson A, Fagerberg C, Brasch-Andersen C, Kibæk M, Bader I, Hernan R, High FA, Chung WK, Schieving JH, Behunova J, Smogavec M, Laccone F, Witsch-Baumgartner M, Zobel J, Duba HC, Weis D.

Genes (Basel). 2022 Jan 15;13(1):154. doi: 10.3390/genes13010154. ABSTRACT POGZ-related disorders (also known as White-Sutton syndrome) encompass a wide range of neurocognitive abnormalities and other accompanying anomalies. Disease severity varies widely among POGZ patients and studies investigating genotype-phenotype association are scarce. Therefore, our aim was to collect data on previously unreported POGZ patients and perform a large-scale phenotype-genotype comparison from published data. Overall, 117 POGZ patients’ genotype and phenotype data were included in the analysis, including 12 novel patients. A severity scoring system was developed for the comparison. Mild and severe phenotypes were compared with the types and location of the variants and the predicted presence or absence of nonsense-mediated RNA decay (NMD). Missense variants were more often associated with mild phenotypes (p = 0.0421) and truncating variants predicted to escape NMD presented with more severe phenotypes (p < 0.0001). Within this group, variants in the prolin-rich region of the POGZ protein were associated with the most severe phenotypes (p = 0.0004). Our study suggests that gain-of-function or dominant negative effect through escaping NMD and the location of the variants in the prolin-rich domain of the protein may play an important role in the severity of manifestations of POGZ-associated neurodevelopmental disorders. PMID:35052493 | DOI:10.3390/genes13010154

January 15, 2022

Expanding the phenotypic and molecular spectrum of NFS1-related disorders that cause functional deficiencies in mitochondrial and cytosolic iron-sulfur cluster containing enzymes

Yang JH, Friederich MW, Ellsworth KA, Frederick A, Foreman E, Malicki D, Dimmock D, Lenberg J, Prasad C, Yu AC, Anthony Rupar C, Hegele RA, Manickam K, Koboldt DC, Crist E, Choi SS, Farhan SMK, Harvey H, Sattar S, Karp N, Wong T, Haas R, Van Hove JLK, Wigby K.

Hum Mutat. 2022 Jan 13. doi: 10.1002/humu.24330. Online ahead of print. ABSTRACT Iron-sulfur cluster proteins are involved in critical functions for gene expression regulation and mitochondrial bioenergetics including the oxidative phosphorylation system. The c.215G>A p.(Arg72Gln) variant in NFS1 has been previously reported to cause infantile mitochondrial complex II and III deficiency. We describe three additional unrelated patients with the same missense variant. Two infants with the same homozygous variant presented with hypotonia, weakness and lactic acidosis, and one patient with compound heterozygous p.(Arg72Gln) and p.(Arg412His) variants presented as a young adult with gastrointestinal symptoms and fatigue. Skeletal muscle biopsy from patients 1 and 3 showed abnormal mitochondrial morphology, and functional analyses demonstrated decreased activity in respiratory chain complex II and variably in complexes I and III. We found decreased mitochondrial and cytosolic aconitase activities but only mildly affected lipoylation of pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase enzymes. Our studies expand the phenotypic spectrum and provide further evidence for the pathogenicity and functional sequelae of NFS1-related disorders with disturbances in both mitochondrial and cytosolic iron-sulfur cluster containing enzymes. PMID:35026043 | DOI:10.1002/humu.24330

January 13, 2022
Rare Disease

DNA methylation episignature in Gabriele-de Vries syndrome

Cherik F, Reilly J, Kerkhof J, Levy M, McConkey H, Barat-Houari M, Butler KM, Coubes C, Lee JA, Le Guyader G, Louie RJ, Patterson WG, Tedder ML, Bak M, Hammer TB, Craigen W, Démurger F, Dubourg C, Fradin M, Franciskovich R, Frengen E, Friedman J, Palares NR, Iascone M, Misceo D, Monin P, Odent S, Philippe C, Rouxel F, Saletti V, Strømme P, Thulin PC, Sadikovic B, Genevieve D.

Genet Med. 2022 Jan 10:S1098-3600(21)05422-8. doi: 10.1016/j.gim.2021.12.003. Online ahead of print. ABSTRACT PURPOSE: Gabriele-de Vries syndrome (GADEVS) is a rare genetic disorder characterized by developmental delay and/or intellectual disability, hypotonia, feeding difficulties, and distinct facial features. To refine the phenotype and to better understand the molecular basis of the syndrome, we analyzed clinical data and performed genome-wide DNA methylation analysis of a series of individuals carrying a YY1 variant. METHODS: Clinical data were collected for 13 individuals not yet reported through an international call for collaboration. DNA was collected for 11 of these individuals and 2 previously reported individuals in an attempt to delineate a specific DNA methylation signature in GADEVS. RESULTS: Phenotype in most individuals overlapped with the previously described features. We described 1 individual with atypical phenotype, heterozygous for a missense variant in a domain usually not involved in individuals with YY1 pathogenic missense variations. We also described a specific peripheral blood DNA methylation profile associated with YY1 variants. CONCLUSION: We reported a distinct DNA methylation episignature in GADEVS. We expanded the clinical profile of GADEVS to include thin/sparse hair and cryptorchidism. We also highlighted the utility of DNA methylation episignature analysis for classification of variants of unknown clinical significance. PMID:35027293 | DOI:10.1016/j.gim.2021.12.003

January 10, 2022
Rare Disease

Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Scala M, Wortmann SB, Kaya N, Stellingwerff MD, Pistorio A, Glamuzina E, van Karnebeek CD, Skrypnyk C, Iwanicka-Pronicka K, Piekutowska-Abramczuk D, Ciara E, Tort F, Sheidley B, Poduri A, Jayakar P, Jayakar A, Upadia J, Walano N, Haack TB, Prokisch H, Aldhalaan H, Karimiani EG, Yildiz Y, Ceylan AC, Santiago-Sim T, Dameron A, Yang H, Toosi MB, Ashrafzadeh F, Akhondian J, Imannezhad S, Mirzadeh HS, Maqbool S, Farid A, Al-Muhaizea MA, Alshwameen MO, Aldowsari L, Alsagob M, Alyousef A, AlMass R, AlHargan A, Alwadei AH, AlRasheed MM, Colak D, Alqudairy H, Khan S, Lines MA, García Cazorla MÁ, Ribes A, Morava E, Bibi F, Haider S, Ferla MP, Taylor JC, Alsaif HS, Firdous A, Hashem M, Shashkin C, Koneev K, Kaiyrzhanov R, Efthymiou S, Genomics QS, Schmitt-Mechelke T, Ziegler A, Issa MY, Elbendary HM, Striano P, Alkuraya FS, Zaki MS, Gleeson JG, Barakat TS, Bierau J, van der Knaap MS, Maroofian R, Houlden H.

Hum Mutat. 2022 Jan 6. doi: 10.1002/humu.24326. Online ahead of print. ABSTRACT Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals. PMID:34989426 | DOI:10.1002/humu.24326

January 6, 2022


AHDC1 missense mutations in Xia-Gibbs syndrome

Khayat MM, Hu J, Jiang Y, Li H, Chander V, Dawood M, Hansen AW, Li S, Friedman J, Cross L, Bijlsma EK, Ruivenkamp CAL, Sansbury FH, Innis JW, O’Shea JO, Meng Q, Rosenfeld JA, McWalter K, Wangler MF, Lupski JR, Posey JE, Murdock D, Gibbs RA.

HGG Adv. 2021 Oct 14;2(4):100049. doi: 10.1016/j.xhgg.2021.100049. Epub 2021 Aug 10. ABSTRACT Xia-Gibbs syndrome (XGS; MIM: 615829) is a phenotypically heterogeneous neurodevelopmental disorder (NDD) caused by newly arising mutations in the AT-Hook DNA-Binding Motif-Containing 1 (AHDC1) gene that are predicted to lead to truncated AHDC1 protein synthesis. More than 270 individuals have been diagnosed with XGS worldwide. Despite the absence of an independent assay for AHDC1 protein function to corroborate potential functional consequences of rare variant genetic findings, there are also reports of individuals with XGS-like trait manifestations who have de novo missense AHDC1 mutations and who have been provided a molecular diagnosis of the disorder. To investigate a potential contribution of missense mutations to XGS, we mapped the missense mutations from 10 such individuals to the AHDC1 conserved protein domain structure and detailed the observed phenotypes. Five newly identified individuals were ascertained from a local XGS Registry, and an additional five were taken from external reports or databases, including one publication. Where clinical data were available, individuals with missense mutations all displayed phenotypes consistent with those observed in individuals with AHDC1 truncating mutations, including delayed motor milestones, intellectual disability (ID), hypotonia, and speech delay. A subset of the 10 reported missense mutations cluster in two regions of the AHDC1 protein with known conserved domains, likely representing functional motifs. Variants outside the clustered regions score lower for computational prediction of their likely damaging effects. Overall, de novo missense variants in AHDC1 are likely diagnostic of XGS when in silico analysis of their position relative to conserved regions is considered together with disease trait manifestations. PMID:34950897 | PMC:PMC8694554 | DOI:10.1016/j.xhgg.2021.100049

December 28, 2021
Rare Disease

Characterization of a patient-derived variant of GPX4 for precision therapy

Liu H, Forouhar F, Seibt T, Saneto R, Wigby K, Friedman J, Xia X, Shchepinov MS, Ramesh SK, Conrad M, Stockwell BR.

Nat Chem Biol. 2021 Dec 20. doi: 10.1038/s41589-021-00915-2. Online ahead of print. ABSTRACT Glutathione peroxidase 4 (GPX4), as the only enzyme in mammals capable of reducing esterified phospholipid hydroperoxides within a cellular context, protects cells from ferroptosis. We identified a homozygous point mutation in the GPX4 gene, resulting in an R152H coding mutation, in three patients with Sedaghatian-type spondylometaphyseal dysplasia. Using structure-based analyses and cell models, including patient fibroblasts, of this variant, we found that the missense variant destabilized a critical loop, which disrupted the active site and caused a substantial loss of enzymatic function. We also found that the R152H variant of GPX4 is less susceptible to degradation, revealing the degradation mechanism of the GPX4 protein. Proof-of-concept therapeutic treatments, which overcome the impaired R152H GPX4 activity, including selenium supplementation, selective antioxidants and a deuterated polyunsaturated fatty acid were identified. In addition to revealing a general approach to investigating rare genetic diseases, we demonstrate the biochemical foundations of therapeutic strategies targeting GPX4. PMID:34931062 | DOI:10.1038/s41589-021-00915-2

December 28, 2021
Rare Disease

Maternal, infant, and environmental risk factors for sudden unexpected infant deaths: results from a large, administrative cohort

Bandoli G, Baer RJ, Owen M, Kiernan E, Jelliffe-Pawlowski L, Kingsmore S, Chambers CD

J Matern Fetal Neonatal Med. 2021 Dec 1:1-8. doi: 10.1080/14767058.2021.2008899. Online ahead of print. ABSTRACT OBJECTIVES: Many studies of sudden unexpected infant death (SUID) have focused on individual domains of risk factors (maternal, infant, and environmental), resulting in limited capture of this multifactorial outcome. The objective of this study was to examine the geographic distribution of SUID in San Diego County, and assess maternal, infant, and environmental risk factors from a large, administrative research platform. STUDY DESIGN: Births in California between 2005 and 2017 were linked to hospital discharge summaries and death files. From this retrospective birth cohort, cases of SUID were identified from infant death files in San Diego County. We estimated adjusted hazard ratios (aHRs) for infant, maternal, and environmental factors and SUID in multivariable Cox regression analysis. Models were adjusted for maternal sociodemographic characteristics and prenatal nicotine exposure. RESULTS: There were 211 (44/100,000 live births; absolute risk 0.04%) infants with a SUID among 484,905 live births. There was heterogeneity in geographic distribution of cases. Multiparity (0.05%; aHR 1.4, 95% confidence interval (CI) 1.1, 1.9), maternal depression (0.11%; aHR 1.8, 95% CI 1.0, 3.4), substance-related diagnoses (0.27%; aHR 2.3, 95% CI 1.3, 3.8), cannabis-related diagnosis (0.35%; aHR 2.7, 95% CI 1.5, 5.0), prenatal nicotine use (0.23%; aHR 2.5, 95% CI 1.5, 4.2), preexisting hypertension (0.11%; aHR 2.3, 95% CI 1.2, 4.3), preterm delivery (0.09%; aHR 2.1, 95% CI 1.5, 3.0), infant with a major malformation (0.09%; aHR 2.0, 95% CI 1.1, 3.6), respiratory distress syndrome (0.12%; aHR 2.6, 95% CI 1.5, 4.6), and select environmental factors were all associated with SUID. CONCLUSIONS: Multiple risk factors were confirmed and expanded upon, and the geographic distribution for SUID in San Diego County was identified. Through this approach, prevention efforts can be targeted to geographies that would benefit the most. PMID:34852708 | DOI:10.1080/14767058.2021.2008899

December 2, 2021
Infant Mortality

Addressing ethical and laboratory challenges for initiation of a rapid whole genome sequencing program

Malone Jenkins S, Palmquist R, Kapron AL, Torr C, Best DH, Karren MA, Brunelli L, Yandell M, Tristani-Firouzi M, Dimmock D, Watts B, Botkin JR, Johnson A, Bonkowsky JL

J Clin Transl Sci. 2021 Aug 9;5(1):e177. doi: 10.1017/cts.2021.833. eCollection 2021. ABSTRACT Rapid whole genome sequencing (rapid WGS) is a powerful diagnostic tool that is becoming increasingly practical for widespread clinical use. However, protocols for its use are challenging to implement. A significant obstacle to clinical adoption is that laboratory certification requires an initial research development phase, which is constrained by regulations from returning results. Regulations preventing return of results have ethical implications in cases which might impact patient outcomes. Here, we describe our experience with the development of a rapid WGS research protocol, that balanced the requirements for laboratory-validated test development with the ethical needs of clinically relevant return of results. PMID:34849253 | PMC:PMC8596074 | DOI:10.1017/cts.2021.833

December 2, 2021

Improved attention linked to sustained phenylalanine reduction in adults with early-treated phenylketonuria

Bilder DA, Arnold GL, Dimmock D, Grant ML, Janzen D, Longo N, Nguyen-Driver M, Jurecki E, Merilainen M, Amato G, Waisbren S

Am J Med Genet A. 2021 Nov 26. doi: 10.1002/ajmg.a.62574. Online ahead of print. ABSTRACT Pegvaliase is approved to reduce phenylalanine (Phe) levels for people with phenylketonuria (PKU). PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862) data were analyzed to evaluate the relationship between Phe and inattention in adult participants with PKU. In the modified-intent-to-treat population (N = 156), baseline mean (SE) plasma Phe was 1263 (29) μmol/L and the Attention Deficit Hyperactivity Disorder Rating Scale-IV Inattentive (IA) symptoms score was 9.8 (0.5). Mean (SE) IA scores fell 9.0 (1.1) in Quartile 1 (Phe reduction between 1166 and 2229 μmol/L) versus 4.3 (0.7) in Quartile 4 (Phe reduction of 139 μmol/L to increase of 934 μmol/L), p = 0.004. Least squares mean (SE) change from baseline IA score was -7.9 (0.7) for participants with final Phe ≤ 360 μmol/L and -4.5 (0.7) for final Phe > 360 μmol/L, p < 0.001. In the inattention subgroup, IA scores fell 13.3 (1.5) in Quartile 1 (Phe reduction between 1288 and 2229 μmol/L) versus 6.2 (1.3) in Quartile 4 (Phe reduction of 247 to increase of 934 μmol/L), p = 0.009. Inattention symptoms improved among those whose Phe levels decreased, particularly those with high baseline IA scores. IA improvements were larger among participants with the greatest plasma Phe reductions, supporting this value as a therapeutic goal. PMID:34826353 | DOI:10.1002/ajmg.a.62574

December 2, 2021
Gene Discovery

Biallelic FRA10AC1 variants cause a neurodevelopmental disorder with growth retardation

von Elsner L, Chai G, Schneeberger PE, Harms FL, Casar C, Qi M, Alawi M, Abdel-Salam GMH, Zaki MS, Arndt F, Yang X, Stanley V, Hempel M, Gleeson JG, Kutsche K

Brain. 2021 Oct 25:awab403. doi: 10.1093/brain/awab403. Online ahead of print. ABSTRACT The major spliceosome mediates pre-mRNA splicing by recognizing the highly conserved sequences at the 5′ and 3′ splice sites and the branch point. More than 150 proteins participate in the splicing process and are organized in the spliceosomal A, B, and C complexes. FRA10AC1 is a peripheral protein of the spliceosomal C complex and its ortholog in the green alga facilitates recognition or interaction with splice sites. We identified biallelic pathogenic variants in FRA10AC1 in five individuals from three consanguineous families. The two unrelated patients 1 and 2 with loss-of-function variants showed developmental delay, intellectual disability, and no speech, while three siblings with the c.494_496delAAG (p.Glu165del) variant had borderline to mild intellectual disability. All patients had microcephaly, hypoplasia or agenesis of the corpus callosum, growth retardation, and craniofacial dysmorphism. FRA10AC1 transcripts and proteins were drastically reduced or absent in fibroblasts of patients 1 and 2. In a heterologous expression system, the p. Glu165del variant impacts intrinsic stability of FRA10AC1 but does not affect its nuclear localization. By co-immunoprecipitation, we found ectopically expressed HA-FRA10AC1 in complex with endogenous DGCR14, another component of the spliceosomal C complex, while the splice factors CHERP, NKAP, RED, and SF3B2 could not be co-immunoprecipitated. Using an in vitro splicing reporter assay, we did not obtain evidence for FRA10AC1 deficiency to suppress missplicing events caused by mutations in the highly conserved dinucleotides of 5′ and 3′ splice sites in an in vitro splicing assay in patient-derived fibroblasts. Our data highlight the importance of specific peripheral spliceosomal C complex proteins for neurodevelopment. It remains possible that FRA10AC1 may have other and/or additional cellular functions, such as coupling of transcription and splicing reactions. PMID:34694367 | DOI:10.1093/brain/awab403

October 26, 2021

Publications Question?