The authors thank all the families who participated in this study.
Author contributions
TF: Conceptualization, Investigation, Writing—original draft, Writing—review & editing, Formal analysis, Visualization, Funding acquisition. EAB: Investigations, Writing—review & editing. Both authors read and approved the submitted version.
Conflicts of interest
The authors declare that there are no conflicts of interest.
Ethical approval
Ethical approval was obtained from the Institute Review Board (IRB) of Philadelphia University in Jordan (IRB number 2/1/2024-2025) and complies with the Declaration of Helsinki.
Consent to participate
Signed informed consents were obtained from all participants in this study. Consents were signed by the parents for all children below 16 years.
Consent to publication
Consents were obtained from all families in this study to publish their data anonymously.
Availability of data and materials
The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.
Funding
This study was funded by the Deanship of Scientific Research and Graduate Studies at Philadelphia University in Jordan. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.
References
Gidziela A, Ahmadzadeh YI, Michelini G, Allegrini AG, Agnew-Blais J, Lau LY, et al. A meta-analysis of genetic effects associated with neurodevelopmental disorders and co-occurring conditions.Nat Hum Behav. 2023;7:642–56. [DOI] [PubMed] [PMC]
Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data.Bioinformatics. 2014;30:2114–20. [DOI] [PubMed] [PMC]
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform.Bioinformatics. 2009;25:1754–60. [DOI] [PubMed] [PMC]
Broad Institute. Picard Toolkit [Computer software]. 2019.
Mose LE, Wilkerson MD, Hayes DN, Perou CM, Parker JS. ABRA: improved coding indel detection via assembly-based realignment.Bioinformatics. 2014;30:2813–5. [DOI] [PubMed] [PMC]
Danecek P, Bonfield JK, Liddle J, Marshall J, Ohan V, Pollard MO, et al. Twelve years of SAMtools and BCFtools.Gigascience. 2021;10:giab008. [DOI] [PubMed] [PMC]
Li H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data.Bioinformatics. 2011;27:2987–93. [DOI] [PubMed] [PMC]
Cingolani P, Platts A, Wang le L, Coon M, Nguyen T, Wang L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3.Fly (Austin). 2012;6:80–92. [DOI] [PubMed] [PMC]
Cingolani P, Patel VM, Coon M, Nguyen T, Land SJ, Ruden DM, et al. Using Drosophila melanogaster as a Model for Genotoxic Chemical Mutational Studies with a New Program, SnpSift.Front Genet. 2012;3:35. [DOI] [PubMed] [PMC]
Amberger JS, Bocchini CA, Schiettecatte F, Scott AF, Hamosh A. OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders.Nucleic Acids Res. 2015;43:D789–98. [DOI] [PubMed] [PMC]
Amberger JS, Bocchini CA, Scott AF, Hamosh A. OMIM.org: leveraging knowledge across phenotype-gene relationships.Nucleic Acids Res. 2019;47:D1038–43. [DOI] [PubMed] [PMC]
Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: improving access to variant interpretations and supporting evidence.Nucleic Acids Res. 2018;46:D1062–7. [DOI] [PubMed] [PMC]
Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation.Nucleic Acids Res. 2001;29:308–11. [DOI] [PubMed] [PMC]
1000 Genomes Project Consortium; Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, et al. A global reference for human genetic variation.Nature. 2015;526:68–74. [DOI] [PubMed] [PMC]
Taliun D, Harris DN, Kessler MD, Carlson J, Szpiech ZA, Torres R, et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.Nature. 2021;590:290–9. [DOI] [PubMed] [PMC]
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al.; Genome Aggregation Database Consortium; Neale BM, Daly MJ, MacArthur DG. The mutational constraint spectrum quantified from variation in 141,456 humans.Nature. 2020;581:434–43. [DOI] [PubMed] [PMC]
NCBI ALFA: Open-Access to dbGaP Aggregated Allele Frequency for Variant Interpretation.NLM Tech Bull. 2020:e5.
Sun KY, Bai X, Chen S, Bao S, Zhang C, Kapoor M, et al.; Regeneron Genetics Center; RGC-ME Cohort Partners; Cantor M, Thornton T, Kang HM, Overton JD, Shuldiner AR, Cremona ML, et al. A deep catalogue of protein-coding variation in 983,578 individuals.Nature. 2024;631:583–92. [DOI] [PubMed] [PMC]
Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect protein function.Nucleic Acids Res. 2003;31:3812–4. [DOI] [PubMed] [PMC]
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations.Nat Methods. 2010;7:248–9. [DOI] [PubMed] [PMC]
Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels.Bioinformatics. 2015;31:2745–7. [DOI] [PubMed] [PMC]
Froukh T, Nafie O, Al Hait SAS, Laugwitz L, Sommerfeld J, Sturm M, et al. Genetic basis of neurodevelopmental disorders in 103 Jordanian families.Clin Genet. 2020;97:621–7. [DOI] [PubMed]
Froukh T, Hawwari A, Al Zubi K. Whole exome sequencing highlights variants in association with Keratoconus in Jordanian families.BMC Med Genet. 2020;21:177. [DOI] [PubMed] [PMC]
Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF, Darbandi SF, Knowles D, Li YI, et al. Predicting Splicing from Primary Sequence with Deep Learning.Cell. 2019;176:535–48.e24. [DOI] [PubMed]
Zeng T, Li YI. Predicting RNA splicing from DNA sequence using Pangolin.Genome Biol. 2022;23:103. [DOI] [PubMed] [PMC]
Chandy KG, Williams CB, Spencer RH, Aguilar BA, Ghanshani S, Tempel BL, et al. A family of three mouse potassium channel genes with intronless coding regions.Science. 1990;247:973–5. [DOI] [PubMed]
Larsen LA, Fosdal I, Andersen PS, Kanters JK, Vuust J, Wettrell G, et al. Recessive Romano-Ward syndrome associated with compound heterozygosity for two mutations in the KVLQT1 gene.Eur J Hum Genet. 1999;7:724–8. [DOI] [PubMed]
Schmidt B, Selmer T, Ingendoh A, von Figura K. A novel amino acid modification in sulfatases that is defective in multiple sulfatase deficiency.Cell. 1995;82:271–8. [DOI] [PubMed]
Froukh T. First Record Mutations in the Genes ASPA and ARSA Causing Leukodystrophy in Jordan.Biomed Res Int. 2019;2019:7235914. [DOI] [PubMed] [PMC]
Grossi S, Regis S, Rosano C, Corsolini F, Uziel G, Sessa M, et al. Molecular analysis of ARSA and PSAP genes in twenty-one Italian patients with metachromatic leukodystrophy: identification and functional characterization of 11 novel ARSA alleles.Hum Mutat. 2008;29:E220–30. [DOI] [PubMed]
Rafi MA, Coppola S, Liu SL, Rao HZ, Wenger DA. Disease-causing mutations in cis with the common arylsulfatase A pseudodeficiency allele compound the difficulties in accurately identifying patients and carriers of metachromatic leukodystrophy.Mol Genet Metab. 2003;79:83–90. [DOI] [PubMed]
Kappler J, von Figura K, Gieselmann V. Late-onset metachromatic leukodystrophy: molecular pathology in two siblings.Ann Neurol. 1992;31:256–61. [DOI] [PubMed]
DaRosa PA, Penchev I, Gumbin SC, Scavone F, Wąchalska M, Paulo JA, et al. UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER.Nature. 2024;627:445–52. [DOI] [PubMed] [PMC]
Ni M, Afroze B, Xing C, Pan C, Shao Y, Cai L, et al. A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental anomalies and epilepsy.Genet Med. 2021;23:900–8. [DOI] [PubMed] [PMC]
Bajaj L, Sharma J, di Ronza A, Zhang P, Eblimit A, Pal R, et al. A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer.J Clin Invest. 2020;130:4118–32. [DOI] [PubMed] [PMC]
Wang SP, Robert MF, Gibson KM, Wanders RJ, Mitchell GA. 3-Hydroxy-3-methylglutaryl CoA lyase (HL): mouse and human HL gene (HMGCL) cloning and detection of large gene deletions in two unrelated HL-deficient patients.Genomics. 1996;33:99–104. [DOI] [PubMed]
Gibson KM, Breuer J, Kaiser K, Nyhan WL, McCoy EE, Ferreira P, et al. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: report of five new patients.J Inherit Metab Dis. 1988;11:76–87. [DOI] [PubMed]
Stambolian D, Ai Y, Sidjanin D, Nesburn K, Sathe G, Rosenberg M, et al. Cloning of the galactokinase cDNA and identification of mutations in two families with cataracts.Nat Genet. 1995;10:307–12. [DOI] [PubMed]
de Winter JP, van der Weel L, de Groot J, Stone S, Waisfisz Q, Arwert F, et al. The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG.Hum Mol Genet. 2000;9:2665–74. [DOI] [PubMed]
Meetei AR, Sechi S, Wallisch M, Yang D, Young MK, Joenje H, et al. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.Mol Cell Biol. 2003;23:3417–26. [DOI] [PubMed] [PMC]
Yoshida L, Nishida S, Shimoyama T, Kawahara T, Rokutan K, Tsunawaki S. Expression of a p67(phox) homolog in Caco-2 cells giving O(2)(-)-reconstituting ability to cytochrome b(558) together with recombinant p47(phox).Biochem Biophys Res Commun. 2002;296:1322–8. [DOI] [PubMed]
Patiño PJ, Rae J, Noack D, Erickson R, Ding J, de Olarte DG, et al. Molecular characterization of autosomal recessive chronic granulomatous disease caused by a defect of the nicotinamide adenine dinucleotide phosphate (reduced form) oxidase component p67-phox.Blood. 1999;94:2505–14. [PubMed]
Morello R, Bertin TK, Chen Y, Hicks J, Tonachini L, Monticone M, et al. CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta.Cell. 2006;127:291–304. [DOI] [PubMed]
Barnes AM, Chang W, Morello R, Cabral WA, Weis M, Eyre DR, et al. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta.N Engl J Med. 2006;355:2757–64. [DOI] [PubMed] [PMC]
Rousso DL, Gaber ZB, Wellik D, Morrisey EE, Novitch BG. Coordinated actions of the forkhead protein Foxp1 and Hox proteins in the columnar organization of spinal motor neurons.Neuron. 2008;59:226–40. [DOI] [PubMed] [PMC]
Hamdan FF, Daoud H, Rochefort D, Piton A, Gauthier J, Langlois M, et al. De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment.Am J Hum Genet. 2010;87:671–8. [DOI] [PubMed] [PMC]