Publications by authors named "Alfonso Caro-Llopis"

11 Publications

  • Page 1 of 1

Prevalence of pathogenic copy number variants among children conceived by donor oocyte.

Sci Rep 2021 03 24;11(1):6752. Epub 2021 Mar 24.

Genetics Unit, Hospital Universitario Y Politecnico La Fe, 46026, Valencia, Spain.

Development of assisted reproductive technologies to address infertility has favored the birth of many children in the last years. The majority of children born with these treatments are healthy, but some concerns remain on the safety of these medical procedures. We have retrospectively analyzed both the fertilization method and the microarray results in all those children born between 2010 and 2019 with multiple congenital anomalies, developmental delay and/or autistic spectrum disorder (n = 486) referred for array study in our center. This analysis showed a significant excess of pathogenic copy number variants among those patients conceived after in vitro fertilization with donor oocyte with respect to those patients conceived by natural fertilization (p = 0.0001). On the other hand, no significant excess of pathogenic copy number variants was observed among patients born by autologous oocyte in vitro fertilization. Further studies are necessary to confirm these results and in order to identify the factors that may contribute to an increased risk of genomic rearrangements, as well as consider the screening for genomic alterations after oocyte donation in prenatal diagnosis.
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http://dx.doi.org/10.1038/s41598-021-86242-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991411PMC
March 2021

Hidden etiology of cerebral palsy: genetic and clinical heterogeneity and efficient diagnosis by next-generation sequencing.

Pediatr Res 2021 08 11;90(2):284-288. Epub 2020 Nov 11.

Neuropediatric Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder that causes movement and postural disabilities. Recent research studies focused on genetic diagnosis in patients with CP of unknown etiology. The present study was carried out in 20 families with one family member affected with idiopathic CP. Chromosomal microarray and exome sequencing techniques were performed in all patients. Chromosomal microarray analysis did not show any pathological or probable pathological structural variant. However, the next-generation sequencing study showed a high diagnostic yield. We report 11/20 patients (55%) with different pathogenic or potentially pathogenic variants detected by exome sequencing analysis: five patients with mutations in genes related to hereditary spastic paraplegia, two with mutations in genes related to Aicardi-Goutières syndrome, three with mutations in genes related to developmental/epileptic encephalopathies, and one with a mutation in the PGK1 gene. The accurate and precise patients' selection, the use of a high-throughput genetic platform, the selection of adequate target genes, and the application of rigorous criteria for the clinical interpretation are the most important elements for a good diagnostic performance. Based on our findings, next-generation sequencing should be considered in patients with cryptogenic CP as the first line of genetic workup. IMPACT: Sequencing techniques in CP of uncertain etiology provides a diagnostic yield of 55%. The appropriate selection of cases optimizes the diagnostic yield. NGS facilitate better understanding of new phenotypes of certain genetic diseases.
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http://dx.doi.org/10.1038/s41390-020-01250-3DOI Listing
August 2021

Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay.

Am J Hum Genet 2019 01 20;104(1):164-178. Epub 2018 Dec 20.

Department of Clinical Genetics, Erasmus Medical Center, 3015 GD Rotterdam, the Netherlands.

SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.
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http://dx.doi.org/10.1016/j.ajhg.2018.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323608PMC
January 2019

A Novel Mutation of in a Patient with Schaaf-Yang Syndrome and Hypopituitarism.

Int J Endocrinol Metab 2018 Jul 1;16(3):e67329. Epub 2018 Jul 1.

Neuropediatric Section, University and Polytechnic Hospital La Fe, Valencia, Spain.

Introduction: Schaaf-Yang syndrome (SYS) is caused by truncating point mutations of the paternal allele of , an imprinted gene located in the critical region of Prader-Willi syndrome (PWS). These patients present a phenotype with neurodevelopmental delay, hypotonia, joint contractures, and a particularly high prevalence of autism (up to 75% in affected individuals). The loss of function of is suggested to contribute to endocrine hypothalamic dysfunction in individuals with PWS.

Case Presentation: The current study presented the case of a patient with SYS and a novel truncating mutation of and phenotypic characteristics typical of this Prader-Willi-like syndrome and also including partial hypopituitarism, hypothyroidism, growth hormone deficiency, and hyperprolactinemia.

Conclusions: The clinical and molecular similarities between SYS and PWS suggested the need for a thorough endocrinological follow-up to improve the prognosis and long-term quality of life for patients with SYS.
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http://dx.doi.org/10.5812/ijem.67329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176277PMC
July 2018

The role of obesity in the fatal outcome of Schaaf-Yang syndrome: Early onset morbid obesity in a patient with a MAGEL2 mutation.

Am J Med Genet A 2018 11 20;176(11):2456-2459. Epub 2018 Sep 20.

Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

Schaaf-Yang syndrome (SYS) was recently identified as a genetic condition resembling Prader-Willi syndrome. It is caused by mutations on the paternal allele of the MAGEL2 gene, a gene that has been mapped in the Prader-Willi critical region. Here, we present an infant with SYS who sadly died because of the combination of hypotonia, sleep apnea, and obesity. A heterozygous premature stop mutation in MAGEL2 was identified in the patient. The main factors reported in the mortality of SYS are lethal arthrogryposis multiplex congenita, fetal akinesia, and pulmonary problems. Our clinical report indicates that obesity and its complications are an important additional factor in the mortality associated with SYS. Therefore, we advise to strictly monitor weight and intensively treat overweight and obesity in SYS.
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http://dx.doi.org/10.1002/ajmg.a.40486DOI Listing
November 2018

Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature.

Am J Med Genet A 2018 11 8;176(11):2259-2275. Epub 2018 Sep 8.

Carle Physician Group, Urbana, Illinois.

De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype-phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype-phenotype correlations.
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http://dx.doi.org/10.1002/ajmg.a.40472DOI Listing
November 2018

HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients.

Eur J Hum Genet 2018 01 27;26(1):64-74. Epub 2017 Nov 27.

Genomics Institute, MultiCare Health System, Tacoma, WA, USA.

Whole-gene duplications and missense variants in the HUWE1 gene (NM_031407.6) have been reported in association with intellectual disability (ID). Increased gene dosage has been observed in males with non-syndromic mild to moderate ID with speech delay. Missense variants reported previously appear to be associated with severe ID in males and mild or no ID in obligate carrier females. Here, we report the largest cohort of patients with HUWE1 variants, consisting of 14 females and 7 males, with 15 different missense variants and one splice site variant. Clinical assessment identified common clinical features consisting of moderate to profound ID, delayed or absent speech, short stature with small hands and feet and facial dysmorphism consisting of a broad nasal tip, deep set eyes, epicanthic folds, short palpebral fissures, and a short philtrum. We describe for the first time that females can be severely affected, despite preferential inactivation of the affected X chromosome. Three females with the c.329 G  >  A p.Arg110Gln variant, present with a phenotype of mild ID, specific facial features, scoliosis and craniosynostosis, as reported previously in a single patient. In these females, the X inactivation pattern appeared skewed in favour of the affected transcript. In summary, HUWE1 missense variants may cause syndromic ID in both males and females.
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http://dx.doi.org/10.1038/s41431-017-0038-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788272PMC
January 2018

Chimeric Genes in Deletions and Duplications Associated with Intellectual Disability.

Int J Genomics 2017 24;2017:4798474. Epub 2017 May 24.

Unidad de Genética, Hospital Universitario y Politécnico La Fe, Avenida de Fernando Abril Martorell 106, 46026 Valencia, Spain.

We report on three nonrelated patients with intellectual disability and CNVs that give rise to three new chimeric genes. All the genes forming these fusion transcripts may have an important role in central nervous system development and/or in gene expression regulation, and therefore not only their deletion or duplication but also the resulting chimeric gene may contribute to the phenotype of the patients. Deletions and duplications are usually pathogenic when affecting dose-sensitive genes. Alternatively, a chimeric gene may also be pathogenic by different gain-of-function mechanisms that are not restricted to dose-sensitive genes: the emergence of a new polypeptide that combines functional domains from two different genes, the deregulated expression of any coding sequence by the promoter region of a neighboring gene, and/or a putative dominant-negative effect due to the preservation of functional domains of partially truncated proteins. Fusion oncogenes are well known, but in other pathologies, the search for chimeric genes is disregarded. According to our findings, we hypothesize that the frequency of fusion transcripts may be much higher than suspected, and it should be taken into account in the array-CGH analyses of patients with intellectual disability.
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http://dx.doi.org/10.1155/2017/4798474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463148PMC
May 2017

High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.

J Med Genet 2017 02 12;54(2):87-92. Epub 2016 Sep 12.

Unidad de Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Background: Intellectual disability is a very complex condition where more than 600 genes have been reported. Due to this extraordinary heterogeneity, a large proportion of patients remain without a specific diagnosis and genetic counselling. The need for new methodological strategies in order to detect a greater number of mutations in multiple genes is therefore crucial.

Methods: In this work, we screened a large panel of 1256 genes (646 pathogenic, 610 candidate) by next-generation sequencing to determine the molecular aetiology of syndromic intellectual disability. A total of 92 patients, negative for previous genetic analyses, were studied together with their parents. Clinically relevant variants were validated by conventional sequencing.

Results: A definitive diagnosis was achieved in 29 families by testing the 646 known pathogenic genes. Mutations were found in 25 different genes, where only the genes KMT2D, KMT2A and MED13L were found mutated in more than one patient. A preponderance of de novo mutations was noted even among the X linked conditions. Additionally, seven de novo probably pathogenic mutations were found in the candidate genes AGO1, JARID2, SIN3B, FBXO11, MAP3K7, HDAC2 and SMARCC2. Altogether, this means a diagnostic yield of 39% of the cases (95% CI 30% to 49%).

Conclusions: The developed panel proved to be efficient and suitable for the genetic diagnosis of syndromic intellectual disability in a clinical setting. Next-generation sequencing has the potential for high-throughput identification of genetic variations, although the challenges of an adequate clinical interpretation of these variants and the knowledge on further unknown genes causing intellectual disability remain to be solved.
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http://dx.doi.org/10.1136/jmedgenet-2016-103964DOI Listing
February 2017

De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy?

Pediatr Res 2016 12 8;80(6):809-815. Epub 2016 Aug 8.

Genetics Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Background: Mutations in the X-linked gene MED12 cause at least three different, but closely related, entities of syndromic intellectual disability. Recently, a new syndrome caused by MED13L deleterious variants has been described, which shows similar clinical manifestations including intellectual disability, hypotonia, and other congenital anomalies.

Methods: Genotyping of 1,256 genes related with neurodevelopment was performed by next-generation sequencing in three unrelated patients and their healthy parents. Clinically relevant findings were confirmed by conventional sequencing.

Results: Each patient showed one de novo variant not previously reported in the literature or databases. Two different missense variants were found in the MED12 or MED13L genes and one nonsense mutation was found in the MED13L gene.

Conclusion: The phenotypic consequences of these mutations are closely related and/or have been previously reported in one or other gene. Additionally, MED12 and MED13L code for two closely related partners of the mediator kinase module. Consequently, we propose the concept of a common MED12/MED13L clinical spectrum, encompassing Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, MED13L haploinsufficiency syndrome, and others.
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http://dx.doi.org/10.1038/pr.2016.162DOI Listing
December 2016

TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations.

Am J Hum Genet 2015 Dec;97(6):922-32

Gene by Gene Ltd., Houston, TX 77008, USA.

We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome.
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http://dx.doi.org/10.1016/j.ajhg.2015.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678794PMC
December 2015
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