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1.
Altern Ther Health Med ; 29(7): 188-199, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37471662

RESUMEN

Background: Uniparental disomy (UPD) is a well-known epigenomic anomaly characterized by the inheritance of both copies of a homologous pair of chromosomes (or part thereof) from the same parent. This genetic condition can have significant implications for prenatal diagnosis and management. Case Presentation: We present a case of a 29-year-old gravida 1 para 0 female who underwent amniocentesis at pregnancy Week 19 due to a high possibility of trisomy chromosome 6, as indicated by noninvasive prenatal testing (NIPT). However, fluorescence in situ hybridization (FISH) and whole-exome sequencing (WES) revealed no abnormalities. Subsequently, chromosomal microarray analysis (CMA) detected uniparental disomy of chromosome 6. Additionally, an ultrasound examination at 28 weeks of gestation revealed intrauterine growth restriction (IUGR). Given these findings, the parents made the decision to terminate the pregnancy. Conclusions: The combination of genetic counseling, FISH, karyotype analysis, WES, CMA, NIPT, and prenatal ultrasound can provide valuable insights for the prenatal diagnosis of UPD. These diagnostic approaches play a crucial role in identifying and managing cases of UPD, primarily when associated with intrauterine growth restrictions.


Asunto(s)
Retardo del Crecimiento Fetal , Disomía Uniparental , Embarazo , Humanos , Femenino , Adulto , Disomía Uniparental/diagnóstico , Disomía Uniparental/genética , Retardo del Crecimiento Fetal/diagnóstico , Retardo del Crecimiento Fetal/genética , Hibridación Fluorescente in Situ , Cromosomas Humanos Par 6 , Mosaicismo , Trisomía
2.
Am J Med Genet A ; 188(6): 1848-1852, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35199468

RESUMEN

This is the first report of the concurrent development of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and Crigler-Najjar syndrome type 1 (CNs1) inherited via uniparental disomy of chromosome 2, which are both autosomal recessive pathologies. Through an expanded newborn metabolic panel, a male infant was identified as having an acylcarnitine pattern typical for LCHADD, later confirmed to be caused by a well-characterized pathogenic variant in the HADHA gene located at 2p23. Prolonged non-hematologic jaundice requiring repetitive phototherapy prompted further genetic analysis, leading to the identification of another genetic abnormality consistent with CNs1, which was caused by a novel pathogenic variant in the UGT1A1 gene located at 2q37. The two identified point mutations in chromosome 2 were homozygous and present on separate arms, which indicated potential uniparental disomy. Microarray analysis of the genetic material from the patient and his parents confirmed paternal isodisomy of chromosome 2. Further studies are needed to identify other possible pathogenic variants located on the same defective chromosome, evaluate the combined effect of the two metabolic abnormalities, and plan the best possible treatment and care.


Asunto(s)
Síndrome de Crigler-Najjar , Cardiomiopatías , Cromosomas Humanos Par 2/genética , Síndrome de Crigler-Najjar/genética , Humanos , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico , Masculino , Miopatías Mitocondriales , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades del Sistema Nervioso , Rabdomiólisis , Disomía Uniparental/genética
3.
Am J Med Genet A ; 179(4): 645-649, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30680869

RESUMEN

TBC1D24-related disorders are rare neurodevelopmental disorders that show a broad range of neuropsychiatric deficits and are mostly inherited in an autosomal recessive manner. Here we describe a case with early-onset epileptic encephalopathy, in whom exome sequencing detected a novel pathogenic homozygous c.442G>A, p.(Glu148Lys) variant in TBC1D24. She showed severe developmental delay, congenital sensorineural hearing loss and seizures, but the combination of a high dose phenobarbital and potassium bromide was very effective for the seizures. Sanger sequencing revealed that her mother was a heterozygous carrier of the TBC1D24 variant, but her father showed only wild-type alleles. Homozygosity mapping analysis using exome data showed loss of the heterozygosity region at 16p13.3-p13.13 encompassing TBC1D24. Genotyping analysis using rare variants within loss of the heterozygosity region indicated that the patient has a homozygous haplotype inherited from her mother, indicating maternal segmental uniparental isodisomy (UPiD). These data clearly show that exome sequencing is a powerful tool to perform comprehensive genetic analysis.


Asunto(s)
Proteínas Activadoras de GTPasa/genética , Homocigoto , Mutación , Espasmos Infantiles/etiología , Disomía Uniparental/patología , Exoma , Femenino , Humanos , Lactante , Pronóstico , Espasmos Infantiles/patología , Disomía Uniparental/genética
4.
J Thromb Haemost ; 14(12): 2410-2418, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27681307

RESUMEN

Essentials Vitamin K-dependent coagulant factor deficiency (VKCFD) is a rare autosomal recessive disorder. We describe a case of inherited VKCFD due to uniparental disomy. The homozygous mutation caused the absence of GGCX isoform 1 and overexpression of Δ2GGCX. Hepatic and non-hepatic vitamin K-dependent proteins must be assayed to monitor VKCFD treatment. SUMMARY: Background Inherited deficiency of all vitamin K-dependent coagulant factors (VKCFD) is a rare autosomal recessive disorder caused by mutations in the γ-glutamyl carboxylase gene (GGCX) or the vitamin K epoxide reductase gene (VKORC1), with great heterogeneity in terms of both clinical presentation and response to treatment. Objective To characterize the molecular basis of VKCFD in a Spanish family. Methods and Results Sequencing of candidate genes, comparative genomic hybridization and massive sequencing identified a new mechanism causing VKCFD in the proband. Uniparental disomy (UPD) of chromosome 2 caused homozygosity of a mutation (c.44-1G>A) resulting in aberrant GGCX splicing. This change contributed to absent expression of the mRNA coding for the full-length protein, and to four-fold overexpression of the smaller mRNA isoform lacking exon 2 (Δ2GGCX). Δ2GGCX might be responsible for two unexpected clinical observations in the patient: (i) increased plasma osteocalcin levels following vitamin K1 supplementation; and (ii) a mild non-bleeding phenotype. Conclusions Our study identifies a new autosomal disease, VKCFD1, caused by UPD. These data suggest that the Δ2GGCX isoform may retain enzymatic activity, and strongly encourage the evaluation of both hepatic and non-hepatic vitamin K-dependent proteins to assess differing responses to vitamin K supplementation in VKCFD patients.


Asunto(s)
Coagulación Sanguínea , Disomía Uniparental , Vitamina K Epóxido Reductasas/deficiencia , Vitamina K/metabolismo , Ligasas de Carbono-Carbono/genética , Hibridación Genómica Comparativa , Femenino , Hemostasis , Homocigoto , Humanos , Lactante , Pérdida de Heterocigocidad , Masculino , Mutación , Fenotipo , Regiones Promotoras Genéticas , ARN Mensajero/metabolismo , España , Vitamina K Epóxido Reductasas/genética
5.
PLoS One ; 10(8): e0136332, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26295707

RESUMEN

Common bermudagrass [C. dactylon (L.) Pers. var. dactylon] is economically and environmentally the most important member among Cynodon species because of its extensive use for turf, forage and soil erosion control in the world. However, information regarding the inheritance within the taxon is limited. Accordingly, the objective of this study was to determine qualitative inheritance mode in common bermudagrass. Two tetraploid (2n = 4x = 36), first-generation selfed (S1) populations, 228 progenies of 'Zebra' and 273 from A12359, were analyzed for segregation with 21 and 12 simple sequence repeat (SSR) markers, respectively. It is concluded that the inheritance mode of tetraploid bermudagrass was complete or near complete disomic. It is evident that the two bermudagrass parents had an allotetraploid genome with two distinct subgenomes since 33 SSR primer pairs amplified 34 loci, each having two alleles. Severe transmission ratio distortions occurred in the Zebra population while less so in the A12359 population. The findings of disomic inheritance and segregation ratio distortion in common bermudagrass is significant in subsequent linkage map construction, quantitative trait locus mapping and marker-assisted selection in the species.


Asunto(s)
Cynodon/genética , Marcadores Genéticos/genética , Repeticiones de Microsatélite/genética , Disomía Uniparental/genética , Segregación Cromosómica/genética , Cromosomas de las Plantas/genética , Genética de Población , Genoma de Planta/genética , Tetraploidía
6.
PLoS One ; 10(7): e0131157, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26153892

RESUMEN

CONTEXT: Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is an autosomal recessive disease caused by biallelic mutations in the vitamin D receptor (VDR) gene. No patients have been reported with uniparental disomy (UPD). OBJECTIVE: Using genome-wide single nucleotide polymorphism (SNP) array to confirm whether HVDRR was caused by UPD of chromosome 12. MATERIALS AND METHODS: A 2-year-old girl with alopecia and short stature and without any family history of consanguinity was diagnosed with HVDRR by typical laboratory data findings and clinical features of rickets. Sequence analysis of VDR was performed, and the origin of the homozygous mutation was investigated by target SNP sequencing, short tandem repeat analysis, and genome-wide SNP array. RESULTS: The patient had a homozygous p.Arg73Ter nonsense mutation. Her mother was heterozygous for the mutation, but her father was negative. We excluded gross deletion of the father's allele or paternal discordance. Genome-wide SNP array of the family (the patient and her parents) showed complete maternal isodisomy of chromosome 12. She was successfully treated with high-dose oral calcium. CONCLUSIONS: This is the first report of HVDRR caused by UPD, and the third case of complete UPD of chromosome 12, in the published literature. Genome-wide SNP array was useful for detecting isodisomy and the parental origin of the allele. Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders. Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.


Asunto(s)
Cromosomas Humanos Par 12 , Polimorfismo de Nucleótido Simple , Raquitismo Hipofosfatémico/diagnóstico , Raquitismo Hipofosfatémico/genética , Disomía Uniparental/genética , Vitamina D/análogos & derivados , Administración Oral , Alelos , Alopecia/genética , Estatura , Calcio/administración & dosificación , Preescolar , Suplementos Dietéticos , Femenino , Genoma Humano , Trastornos del Crecimiento/genética , Heterocigoto , Homocigoto , Humanos , Hidroxicolecalciferoles/administración & dosificación , Mutación , Vitamina D/metabolismo
7.
Orphanet J Rare Dis ; 6: 78, 2011 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-22104167

RESUMEN

BACKGROUND: Anderson's Disease (AD)/Chylomicron Retention Disease (CMRD) is a rare hereditary hypocholesterolemic disorder characterized by a malabsorption syndrome with steatorrhea, failure to thrive and the absence of chylomicrons and apolipoprotein B48 post-prandially. All patients studied to date exhibit a mutation in the SAR1B gene, which codes for an essential component of the vesicular coat protein complex II (COPII) necessary for endoplasmic reticulum to Golgi transport. We describe here a patient with AD/CMRD, a normal SAR1B gene protein coding sequence and maternal uniparental disomy of chromosome 7 (matUPD7). METHODS AND RESULTS: The patient, one of two siblings of a Japanese family, had diarrhea and steatorrhea beginning at five months of age. There was a white duodenal mucosa upon endoscopy. Light and electron microscopy showed that the intestinal villi were normal but that they had lipid laden enterocytes containing accumulations of lipid droplets in the cytoplasm and lipoprotein-size particles in membrane bound structures. Although there were decreased amounts in plasma of total- and low-density lipoprotein cholesterol, apolipoproteins AI and B and vitamin E levels, the triglycerides were normal, typical of AD/CMRD. The presence of low density lipoproteins and apolipoprotein B in the plasma, although in decreased amounts, ruled out abetalipoproteinemia. The parents were asymptomatic with normal plasma cholesterol levels suggesting a recessive disorder and ruling out familial hypobetalipoproteinemia. Sequencing of genomic DNA showed that the 8 exons of the SAR1B gene were normal. Whole genome SNP analysis and karyotyping revealed matUPD7 with a normal karyotype. In contrast to other cases of AD/CMRD which have shown catch-up growth following vitamin supplementation and a fat restricted diet, our patient exhibits continued growth delay and other aspects of the matUPD7 and Silver-Russell Syndrome phenotypes. CONCLUSIONS: This patient with AD/CMRD has a normal SAR1B gene protein coding sequence which suggests that factors other than the SAR1B protein may be crucial for chylomicron secretion. Further, this patient exhibits matUPD7 with regions of homozygosity which might be useful for elucidating the molecular basis of the defect(s) in this individual. The results provide novel insights into the relation between phenotype and genotype in these diseases and for the mechanisms of secretion in the intestine.


Asunto(s)
Hipobetalipoproteinemias/patología , Síndromes de Malabsorción/patología , Proteínas de Unión al GTP Monoméricas/genética , Trisomía/patología , Disomía Uniparental/patología , Pueblo Asiatico/genética , Biopsia , Preescolar , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 7/metabolismo , Endoscopía , Humanos , Hipobetalipoproteinemias/genética , Hipobetalipoproteinemias/metabolismo , Mucosa Intestinal/metabolismo , Síndromes de Malabsorción/genética , Síndromes de Malabsorción/metabolismo , Masculino , Proteínas de Unión al GTP Monoméricas/química , Proteínas de Unión al GTP Monoméricas/metabolismo , Mosaicismo , Fenotipo , Análisis de Secuencia de ADN , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/metabolismo , Síndrome de Silver-Russell/patología , Esteatorrea/genética , Esteatorrea/metabolismo , Esteatorrea/patología , Trisomía/genética , Disomía Uniparental/genética
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