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This work was funded by the Instituto de Salud Carlos III (ISCIII), the European Regional Development Fund [PI19/01155] and the Consejeria de Educacion, Juventud y Deporte, Comunidad de Madrid [B2017/BMD3721].

Analysis of institutional authors

Soriano-Sexto, AlejandroAuthorGallego, DianaAuthorNavarrete, RosaAuthorUgarte, MagdalenaAuthorRodriguez-Pombo, PilarAuthorPerez, BelenCorresponding Author

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Article

Identification of Clinical Variants beyond the Exome in Inborn Errors of Metabolism

Publicated to:INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. 23 (21): 12850 - - 2022-11-01 23(21), DOI: 10.3390/ijms232112850

Authors: Soriano-Sexto, Alejandro; Gallego, Diana; Leal, Fatima; Castejon-Fernandez, Natalia; Navarrete, Rosa; Alcaide, Patricia; Couce, Maria L; Martin-Hernandez, Elena; Quijada-Fraile, Pilar; Pena-Quintana, Luis; Yahyaoui, Raquel; Correcher, Patricia; Ugarte, Magdalena; Rodriguez-Pombo, Pilar; Perez, Belen

Affiliations

Hosp Univ 12 Octubre, Ctr Referencia Nacl CSUR & Europeo MetabERN Para, Serv Pediat, Unidad Enfermedades Mitocondriales Metab Heredita, Madrid 28041, Spain - Author
Hosp Univ La Fe, Nutr & Metabolophaties Unit, Valencia 46026, Spain - Author
Malaga Reg Univ Hosp, Inst Biomed Res Malaga IBIMA Plafatorma BIONAND, Lab Metab Disorders & Newborn Screening, IBIMA RARE, Malaga 29010, Spain - Author
Univ Autonoma Madrid, Dept Biol Mol, Ctr Biol Mol,Ctr Diagnost Enfermedades Mol,IdiPAZ, Ctr Invest Biomed Red Enfermedades Raras CIBERER, E-28049 Madrid, Spain - Author
Univ Las Palmas Gran Canaria, Complejo Hosp Univ Insular Maternoifantil CHUIMI, Ctr Invest Biomed Red Fisiopatol Obesidad &, Hepatol & Nutr Unit,Pediat Gastroenterol,Asociac, Gran Canaria 35016, Spain - Author
Univ Santiago de Compostela, Clin Univ Hosp Santiago de Compostela, Hlth Res Inst Santiago de Compostela,MetabERN, Unit Diag & Treatment Congenital Metab Dis,CIBERE, Santiago De Compostela 15706, Spain - Author
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Abstract

Inborn errors of metabolism (IEM) constitute a huge group of rare diseases affecting 1 in every 1000 newborns. Next-generation sequencing has transformed the diagnosis of IEM, leading to its proposed use as a second-tier technology for confirming cases detected by clinical/biochemical studies or newborn screening. The diagnosis rate is, however, still not 100%. This paper reports the use of a personalized multi-omics (metabolomic, genomic and transcriptomic) pipeline plus functional genomics to aid in the genetic diagnosis of six unsolved cases, with a clinical and/or biochemical diagnosis of galactosemia, mucopolysaccharidosis type I (MPS I), maple syrup urine disease (MSUD), hyperphenylalaninemia (HPA), citrullinemia, or urea cycle deficiency. Eight novel variants in six genes were identified: six (four of them deep intronic) located in GALE, IDUA, PTS, ASS1 and OTC, all affecting the splicing process, and two located in the promoters of IDUA and PTS, thus affecting these genes' expression. All the new variants were subjected to functional analysis to verify their pathogenic effects. This work underscores how the combination of different omics technologies and functional analysis can solve elusive cases in clinical practice.

Keywords

allelic expression imbalancedifferential gene expressioninherited metabolic disordersmulti-omicsAllelic expression imbalanceCollegeDifferential gene expressionEnhancerExomeExome sequencingGeneGenomicsHumansInfant, newbornInherited metabolic disordersMaple syrup urine diseaseMessenger-rnaMetabolism, inborn errorsMulti-omicsMutationsNeonatal screeningSyrup-urine-diseaseTargeted transcriptomics

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2022, it was in position 66/285, thus managing to position itself as a Q1 (Primer Cuartil), in the category Biochemistry & Molecular Biology.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.05. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 1.38 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 2.79 (source consulted: Dimensions Jun 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-06-20, the following number of citations:

  • WoS: 5
  • Scopus: 8
  • Europe PMC: 2
  • OpenCitations: 5

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-20:

  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 22 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

    It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

    • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
    • Assignment of a Handle/URN as an identifier within the deposit in the Institutional Repository: https://repositorio.uam.es/handle/10486/706570

    Leadership analysis of institutional authors

    There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (SORIANO SEXTO, ALEJANDRO) and Last Author (PEREZ GONZALEZ, MARIA BELEN).

    the author responsible for correspondence tasks has been PEREZ GONZALEZ, MARIA BELEN.