RESUMEN
Silver-Russell syndrome (SRS) is a congenital disorder characterized by prenatal and postnatal growth failure and craniofacial features. Hypomethylation of the H19/IGF2:IG-differential methylated region (H19LOM) is observed in 50% of SRS patients, and 15% of SRS patients with H19LOM had multilocus imprinting disturbance (MLID). Schimke immuno-osseous dysplasia (SIOD), characterized by spondyloepiphyseal dysplasia and nephropathy, is an autosomal recessive disorder caused by mutations in SMARCAL1 on chromosome 2. We report a patient with typical SRS-related features, spondyloepiphyseal dysplasia, and severe nephropathy. Molecular analyses showed H19LOM, paternal uniparental isodisomy of chromosome 2 (iUPD(2)pat), and a paternally inherited homozygous frameshift variant in SMARCAL1. Genome-wide methylation analysis showed MLID in this patient, although it showed no MLID in another patient with SIOD without SRS phenotype. These results suggest that iUPD(2)pat unmasked the recessive mutation in SMARCAL1 and that the SMARCAL1 gene mutation may have no direct effect on the patient's methylation defects.
Asunto(s)
Arteriosclerosis/genética , ADN Helicasas/genética , Metilación de ADN/genética , Síndrome Nefrótico/genética , Osteocondrodisplasias/genética , Enfermedades de Inmunodeficiencia Primaria/genética , Embolia Pulmonar/genética , Síndrome de Silver-Russell/genética , Arteriosclerosis/complicaciones , Arteriosclerosis/fisiopatología , Niño , Preescolar , Cromosomas Humanos Par 2/genética , Femenino , Genoma Humano/genética , Impresión Genómica/genética , Humanos , Recién Nacido , Masculino , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/fisiopatología , Osteocondrodisplasias/complicaciones , Osteocondrodisplasias/fisiopatología , Fenotipo , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Enfermedades de Inmunodeficiencia Primaria/fisiopatología , Embolia Pulmonar/complicaciones , Embolia Pulmonar/fisiopatología , Síndrome de Silver-Russell/complicaciones , Síndrome de Silver-Russell/fisiopatología , Disomía Uniparental/genética , Disomía Uniparental/fisiopatologíaRESUMEN
Uniparental disomy (UPD) is defined as two copies of a whole chromosome derived from the same parent. There can be multiple mechanisms that lead to UPD; these are reviewed in the context of contemporary views on the mechanism leading to aneuploidy. Recent studies indicate that UPD is rare in an apparently healthy population and also rare in spontaneous abortion tissues. The most common type of UPD is a maternal heterodisomy (both maternal allele sets present). Isodisomy (a duplicated single set of alleles) or segmental loss of heterozygosity is sometimes encountered in SNP-based microarray referrals. Decisions regarding the most appropriate follow-up testing should consider the possibility of consanguinity (that will generally involve multiple regions), an imprinted gene disorder (chromosomes 6, 7, 11, 14, 15, 20), expression of an autosomal recessive disorder, and an occult aneuploid cell line that may be confined to the placenta. Upd(16)mat, per se, does not appear to be associated with an abnormal phenotype. UPD provides an insight into the history of early chromosome segregation error and understanding the rates and fate of these events are of key importance in the provision of fertility management and prenatal healthcare.
Asunto(s)
Disomía Uniparental/etiología , Disomía Uniparental/genética , Adulto , Femenino , Humanos , Embarazo , Disomía Uniparental/fisiopatologíaRESUMEN
OBJECTIVE: To evaluate the risk of fetal involvement when trisomy 8 mosaicism (T8M) is detected in chorionic villus samples (CVS). METHODS: A retrospective descriptive study of registered pregnancies in Denmark with T8M in CVS identified through a database search and a review of published cases of T8M found through a systematic literature search and inclusion of cross references. Pregnancies with T8M in CVS and no additional numerical chromosomal aberrations were included. RESULTS: A total of 37 Danish cases and 60 published cases were included. T8M detected in a CVS was associated with fetal involvement in 18 out of 97 pregnancies (18.6% [95%CI: 11.4-27.7]). Eight out of 70 (11.4% [95%CI: 5.1-21.3]) interpreted prenatally to be confined placental mosaicism (CPM) were subsequently found to be true fetal mosaicisms (TFM). CONCLUSION: T8M detected in CVS poses a significant risk of fetal involvement, and examination of amniotic fluid (AF) and/or fetal tissue should be offered. However, a normal result of AF still has a considerable residual risk of fetal involvement. Genetic counselling at an early gestational age is essential, and follow-up ultrasonography should be performed to predict fetal involvement if possible.
Asunto(s)
Placenta/fisiopatología , Trisomía/diagnóstico , Disomía Uniparental/diagnóstico , Adulto , Muestra de la Vellosidad Coriónica/métodos , Cromosomas Humanos Par 8 , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Humanos , Mosaicismo , Placenta/anomalías , Embarazo , Sistema de Registros/estadística & datos numéricos , Estudios Retrospectivos , Trisomía/fisiopatología , Disomía Uniparental/fisiopatologíaRESUMEN
BACKGROUND: Pediatric myelodysplastic syndromes (MDS) display clonal genomic instability that can lead to acquisition of other hematological disorders, usually by loss of heterozygosity. Immunodeficiency caused by uniparental disomy (UPD) has not previously been reported. METHODS: We investigated a 13-year-old boy who suffered from recurrent infections and pancytopenia for 1 year. Both the comet assay and chromosome breakage analysis were normal, but the bone marrow showed evidence of dysplasia characteristic of MDS. With his normal sister as donor, he underwent failed hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning (RIC) followed by successful HSCT with myeloablative conditioning (MAC). We used single nucleotide polymorphism (SNP) array, targeted gene panel, and whole exome sequencing to investigate the etiology of his disease. RESULTS: The molecular analyses revealed multiple regions of homozygosity, one region encompassing a homozygous missense variant of recombination activating gene 1 (RAG1) which was previously associated with severe immunodeficiency in infancy. This RAG1 mutation was heterozygous in the proband's fingernail DNA, but was changed to homozygous in the proband's marrow by somatic acquisition of UPD event. No other pathogenic driver mutation for MDS-related genes was identified. CONCLUSION: The hematological phenotype, somatic genomic instability, and response to HSCT MAC but not HSCT RIC deduced to a diagnosis of MDS type refractory cytopenia of children in this patient. His immunodeficiency was secondary to MDS due to somatic acquisition of homozygosity for known pathogenic RAG1 mutation.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/patología , Mutación , Síndromes Mielodisplásicos/patología , Disomía Uniparental/fisiopatología , Síndrome de Inmunodeficiencia Adquirida/etiología , Síndrome de Inmunodeficiencia Adquirida/terapia , Adolescente , Trasplante de Células Madre Hematopoyéticas , Proteínas de Homeodominio/genética , Humanos , Masculino , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/terapia , PronósticoRESUMEN
Pediatric patients with Prader-Willi syndrome (PWS) can be treated with recombinant human GH (rhGH). These patients are highly sensitive to rhGH and the standard doses suggested by the international guidelines often result in IGF-1 above the normal range. We aimed to evaluate 1 the proper rhGH dose to optimize auxological outcomes and to avoid potential overtreatment, and 2 which patients are more sensitive to rhGH. In this multicenter real-life study, we recruited 215 patients with PWS older than 1â¯year, on rhGH at least for 6â¯months, from Italian Centers for PWS care. We collected auxological parameters, rhGH dose, IGF-1 at recruitment and (when available) at start of treatment. The rhGH dose was 4.3 (0.7/8.4) mg/m2/week. At recruitment, IGF-1 was normal in 72.1% and elevated in 27.9% of the patients. In the group of 115 patients with IGF-1 available at start of rhGH, normal pretreatment IGF-1 and uniparental disomy were associated with elevated IGF-1 during the therapy. No difference in height and growth velocity was found between patients treated with the highest and the lowest range dose. The rhGH dose prescribed in Italy seems lower than the recommended one. Normal pretreatment IGF-1 and uniparental disomy are risk factors for elevated IGF-1. The latter seems to be associated with higher sensitivity to GH. In case of these risk factors, we recommend a more accurate titration of the dose to avoid overtreatment and its potential side effects.
Asunto(s)
Hormona de Crecimiento Humana/administración & dosificación , Factor I del Crecimiento Similar a la Insulina/metabolismo , Síndrome de Prader-Willi/patología , Disomía Uniparental/fisiopatología , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Síndrome de Prader-Willi/tratamiento farmacológico , Síndrome de Prader-Willi/metabolismo , PronósticoRESUMEN
Pancreatoblastoma is a rare type of pancreatic cancer in children. Here, we describe a case in which Beckwith-Wiedemann syndrome (BWS) was first suspected because of placental mesenchymal dysplasia. Although the baby did not show the stigmata characteristic of BWS or abnormal peripheral blood methylation, she developed a massive pancreatoblastoma 2 months later. She survived after partial excision of the tumor and chemotherapy. The methylation pattern of the pancreatoblastoma tissue was typical of BWS. Single nucleotide polymorphism (SNP) array analyzes revealed that the pancreatoblastoma tissue had genome-wide loss of maternal alleles. Peripheral blood and nontumor pancreatic tissue showed normal biparental genomic contribution. Interphase fluorescence in situ hybridization analysis with centromeric probes for chromosomes 2 and 11 revealed haploid pancreatoblastoma cells, whereas the placental mesenchymal dysplasia tissue and nontumor pancreas tissue showed diploidy. SNP genotype analysis suggested the presence of mosaicism with the pancreatoblastoma tissue having a different paternal haplotype than that of the peripheral blood and nontumor pancreatic tissue. We report for the first time mosaic paternal haploidy associated with pancreatoblastoma. Babies with placental mesenchymal dysplasia, even those without a definitive diagnosis of BWS, need to be closely followed for the occurrence of embryonic tumors.
Asunto(s)
Síndrome de Beckwith-Wiedemann/genética , Mosaicismo , Neoplasias Pancreáticas/genética , Disomía Uniparental/genética , Síndrome de Beckwith-Wiedemann/fisiopatología , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 2/genética , Metilación de ADN/genética , Femenino , Genotipo , Haploidia , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Mesodermo/patología , Neoplasias Pancreáticas/fisiopatología , Herencia Paterna/genética , Placenta/patología , Polimorfismo de Nucleótido Simple/genética , Embarazo , Disomía Uniparental/fisiopatologíaRESUMEN
PURPOSE: Beckwith-Wiedemann syndrome (BWS) is a human genomic imprinting disorder characterized by lateralized overgrowth, macroglossia, abdominal wall defects, congenital hyperinsulinism, and predisposition to embryonal tumors. One of the molecular etiologies underlying BWS is paternal uniparental isodisomy of chromosome 11p15.5 (pUPD11). About 8% of pUPD11 cases are due to genome-wide paternal uniparental isodisomy (GWpUPD). About 30 cases of live-born patients with GWpUPD have been described, most of whom were mosaic and female. We present male patients with BWS due to GWpUPD, elucidate the underlying mechanism, and make recommendations for management. METHODS: Three male patients with GWpUPD underwent clinical and molecular evaluation by single-nucleotide polymorphism (SNP) microarrays in different tissues. Previously published cases of GWpUPD were reviewed. RESULTS: SNP microarray demonstrated a GWpUPD cell population with sex chromosomes XX and biparental cell population with sex chromosomes XY, consistent with dispermic androgenetic chimerism. CONCLUSION: SNP microarray is necessary to distinguish GWpUPD cases and the underlying mechanisms. The percentage of GWpUPD cell population within a specific tissue type correlated with the amount of tissue dysplasia. Males with BWS due to GWpUPD are important to distinguish from other molecular etiologies because the mechanism indicates risk for germ cell tumors and autosomal recessive diseases in addition to other BWS features.
Asunto(s)
Síndrome de Beckwith-Wiedemann/etiología , Disomía Uniparental/genética , Quimerismo , Cromosomas Humanos Par 11/genética , Metilación de ADN/genética , Impresión Genómica/genética , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Mosaicismo , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Disomía Uniparental/diagnóstico , Disomía Uniparental/fisiopatologíaAsunto(s)
Canal Anal/anomalías , Síndrome del Maullido del Gato/genética , Esófago/anomalías , Cardiopatías Congénitas/genética , Riñón/anomalías , Deformidades Congénitas de las Extremidades/genética , Columna Vertebral/anomalías , Tráquea/anomalías , Trisomía/genética , Disomía Uniparental/genética , Feto Abortado/diagnóstico por imagen , Feto Abortado/fisiopatología , Canal Anal/fisiopatología , Cromosomas Humanos Par 5/genética , Síndrome del Maullido del Gato/fisiopatología , Esófago/fisiopatología , Femenino , Cardiopatías Congénitas/fisiopatología , Humanos , Riñón/fisiopatología , Deformidades Congénitas de las Extremidades/fisiopatología , Mosaicismo , Fenotipo , Embarazo , Columna Vertebral/fisiopatología , Tráquea/fisiopatología , Trisomía/fisiopatología , Disomía Uniparental/fisiopatologíaRESUMEN
BACKGROUND/AIMS: Temple syndrome is an imprinting disorder caused by maternal uniparental disomy of chromosome 14 (mat UPD14), paternal deletion of 14q32 or paternal hypomethylation of the intergenic differentially methylated region (MEG3/DLK1 IG-DMR). Patients with Temple syndrome have pre- and postnatal growth restriction, short stature, hypotonia, small hands and feet and precocious puberty. We sought to determine whether treatment with growth hormone improves growth outcomes in patients with Temple syndrome. METHODS: This was a retrospective observational study reviewing the medical records of 14 patients with Temple syndrome, 7 of whom were treated with growth hormone. RESULTS: After 1 year of growth hormone treatment, the height standard deviation score (SDS) increased a median of 1.31 SDS with a median increased height velocity of 5.30 cm/year. CONCLUSIONS: These results suggest short-term improvement in height SDS with growth hormone treatment similar to the response in patients treated under the small for gestational age indication. We recommend considering growth hormone therapy in all patients with Temple syndrome who have short stature.
Asunto(s)
Cromosomas Humanos Par 14/genética , Metilación de ADN , Trastornos del Crecimiento , Hormona de Crecimiento Humana/administración & dosificación , Disomía Uniparental , Adolescente , Adulto , Niño , Preescolar , Femenino , Trastornos del Crecimiento/tratamiento farmacológico , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/patología , Trastornos del Crecimiento/fisiopatología , Humanos , Lactante , Masculino , Estudios Retrospectivos , Síndrome , Disomía Uniparental/genética , Disomía Uniparental/patología , Disomía Uniparental/fisiopatologíaRESUMEN
Mosaic trisomy 5 is a very rare condition in liveborns, with few cases reported in the last four decades. There are some reports of prenatally diagnosed mosaic trisomy 5 resulting in phenotypically normal offspring, suggesting a low level of mosaicism, but there are also reports associated with multiple congenital anomalies, cardiovascular malformations, and intrauterine growth restriction. We report an infant male diagnosed with mosaic trisomy 5 (5/15 cells) via amniocentesis. The patient was subsequently found to have uniparental disomy 5 (UPD5) by postnatal chromosome microarray, but high-resolution chromosome analysis on peripheral blood did not identify trisomy 5. Dysmorphic features included a tall forehead with low anterior hairline, hypertelorism, low-set ears, and a prominent nose and midface. Other anomalies included bilateral bifid thumbs, hypospadias, a perineal fistula, unilateral multicystic kidney, and decreased subcutaneous fat with loose skin. He had complex congenital heart disease consisting of ventricular and atrial septal defects and polyvalvular defects. The patient died at age one after a prolonged admission. We add this case to the literature with the added benefit of data from a postnatal microarray, which was not available in other cases, to broaden the phenotype of mosaic trisomy 5 and UPD5.With the current available technology, we stress the importance of postnatal genetic testing to confirm prenatal cytogenetic findings in order to further define such phenotypes. This will provide the most accurate information and counseling to affected families.
Asunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Síndrome del Maullido del Gato/diagnóstico , Trisomía/diagnóstico , Disomía Uniparental/genética , Anomalías Múltiples/fisiopatología , Cromosomas Humanos Par 5/genética , Síndrome del Maullido del Gato/genética , Síndrome del Maullido del Gato/fisiopatología , Humanos , Lactante , Masculino , Análisis por Micromatrices , Mosaicismo , Diagnóstico Prenatal , Trisomía/genética , Trisomía/fisiopatología , Disomía Uniparental/diagnóstico , Disomía Uniparental/fisiopatologíaRESUMEN
Chromosomal microarray analysis (CMA) has been used routinely in pediatric and prenatal genetic diagnosis in clinical practice, but it has rarely been applied to miscarriage analysis. In this study, we conducted a prospective study to evaluate the feasibility of CMA for genetic diagnosis of first-trimester miscarriage specimens. We successfully analyzed 551 fresh miscarriage specimens using single-nucleotide polymorphism (SNP) array. Among the specimens, 2.9% (16/551) had significant maternal cell contamination and were excluded from the study. Clinically significant chromosomal abnormalities were identified in 295 (55.1%) cases, including 214 (40%) with aneuploidy, 40 (7.5%) with polyploidy, 19 (3.6%) with partial aneuploidy, 12 (2.2%) with pathogenic microdeletion/microduplication, and 10 (1.9%) with uniparental isodisomy (isoUPD). Variants of uncertain significance were obtained in 15 cases (2.8%). Notably, isoUPD involving a single chromosome (chromosome 22) and two recurrent copy number variations, 22q11.2 microdeletion and 7q11.23 microdeletion, were identified as probably to be associated with miscarriage. The frequency and distribution of genetic aberrations in the spontaneous abortion group was not significantly different from those in the recurrent miscarriage group. Our study suggests SNP array is a reliable, robust, and high-resolution technology for genetic diagnosis of miscarriage in clinical practice.
Asunto(s)
Aborto Habitual/genética , Trastornos de los Cromosomas/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Disomía Uniparental/genética , Aborto Habitual/fisiopatología , Adolescente , Adulto , Aneuploidia , Variaciones en el Número de Copia de ADN/genética , Femenino , Humanos , Cariotipificación , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Embarazo , Primer Trimestre del Embarazo/genética , Diagnóstico Prenatal , Disomía Uniparental/fisiopatologíaRESUMEN
Maternal uniparental disomy of chromosome 16 [upd(16)mat] as the result of trisomy 16 is one of the most frequently reported uniparental disomies in humans, but a consistent phenotype is not obvious. Particularly, it is difficult to discriminate between features resulting from upd(16)mat and mosaic trisomy 16. By evaluating literature data (n = 74) and three own cases we aimed to determine whether the clinical features are due to upd(16)mat or to trisomy 16 mosaicism. While in single cases the clinical symptoms were caused by homozygosity of autosomal recessive mutations on chromosome 16, it turned out that clinical features in upd(16)mat are caused by (hidden) trisomy 16 mosaicism and a specific chromosome 16-associated imprinting disorder does not exist. In trisomy 16/upd(16)mat pregnancies, the management should be based on the ultrasound results and on the clinical course of the pregnancy. In fact, mosaic trisomy 16 pregnancies require a close monitoring because of the higher risk for hypertensive disorders. Postnatal testing for upd(16)mat should be considered in case of homozygosity for an autosomal-recessive mutation, in individuals carrying chromosome 16 aberrations and in phenotypes comprising features of the trisomy 16/upd(16)mat spectrum. Finally, upd(16)mat probably represents a bioindicator for a hidden trisomy 16 mosaicism.
Asunto(s)
Cromosomas Humanos Par 16/genética , Trisomía/genética , Disomía Uniparental/genética , Preescolar , Impresión Genómica/genética , Humanos , Masculino , Herencia Materna/genética , Mosaicismo , Trisomía/fisiopatología , Disomía Uniparental/fisiopatologíaRESUMEN
OBJECTIVE: Uniparental disomy (UPD) is an unusual situation wherein two homologous chromosomes are inherited from the same parent. UPDs can cause clinical abnormalities owing to the aberrant dosage of genes regulated by epigenetic imprinting or homozygosity of variants for recessive phenotypes. The aim of this study was to identify the genetic cause of the obesity and developmental delay phenotype in a 3-year-old Chinese boy. STUDY DESIGN: Chromosomal microarray analysis (CMA) was used for detecting potential copy number variations (CNVs) and homozygous segments. Whole-exome sequencing (WES) identified sequence variants. Sanger sequencing further confirmed the variants in GPBAR1 and CAPN10 both in the patient and the parents. RESULTS: No clinically significant CNVs were identified by CMA but a complete UPD of chromosome 2 (UPD2) was revealed in the patient. WES identified a total of 13 rare homozygous single-nucleotide variants (SNVs) on chromosome 2. Among the 13 SNVs, a nonsense variation in GPBAR1 (c.753T>G; p.Y251*) and a missense variation in CAPN10 (c.413C>T; p.S138F) were evaluated as candidate disease-causing variants based on their functional impacts to their respective protein and the biological relevance of the genes to the clinical presentation of our patient. Both GPBAR1 and CAPN10 variants were detected in the patient's mother in a heterozygous state, indicating that the patient had maternal UPD2. No other clinically relevant variants were identified. CONCLUSIONS: Homozygosity of rare recessive variations caused by UPD2 likely contributed to the phenotypes of our patient. Based on emerging evidence, the nonsense variation in GPBAR1 and the missense variation in CAPN10 are considered as causally related to our patient's phenotype, that is, obesity and delayed development, respectively. The present study further supports the role of GPBAR1 in obesity and the role of calpain-10 in neurological function.
Asunto(s)
Discapacidades del Desarrollo/genética , Obesidad Infantil/genética , Disomía Uniparental/diagnóstico , Anomalías Múltiples , Pueblo Asiatico , Calpaína , Preescolar , China/etnología , Cromosomas Humanos Par 2/genética , Variaciones en el Número de Copia de ADN , Discapacidades del Desarrollo/etiología , Genotipo , Humanos , Masculino , Mutación , Obesidad Infantil/etiología , Análisis por Matrices de Proteínas , Receptores Acoplados a Proteínas G/genética , Disomía Uniparental/genética , Disomía Uniparental/fisiopatologíaRESUMEN
Temple syndrome (TS, MIM 616222) is an imprinting disorder involving genes within the imprinted region of chromosome 14q32. TS is a genetically complex disorder, which is associated with maternal uniparental disomy of chromosome 14 (UPD14), paternal deletions on chromosome 14, or loss of methylation at the intergenic differentially methylated region (IG-DMR). Here, we describe the case of a patient with maternal hetero-UPD14, mixed iso-/hetero-disomy mechanism identified by a single nucleotide polymorphism (SNP) array analysis of patient-father duos study. The phenotype of our case is similarities to Prader-Willi syndrome (PWS) during infancy and to Russell-Silver syndrome (RSS) during childhood. This SNP array appears to be an effective initial screening tool for patients with nonspecific clinical features suggestive of chromosomal disorders.
Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 14/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Polimorfismo de Nucleótido Simple , Disomía Uniparental/genética , Disomía Uniparental/fisiopatología , Anomalías Múltiples/patología , Determinación de la Edad por el Esqueleto , Encéfalo/diagnóstico por imagen , Preescolar , Cara/anomalías , Padre , Deformidades Congénitas de la Mano , Humanos , Masculino , Madres , Fenotipo , Síndrome , Disomía Uniparental/patologíaRESUMEN
BACKGROUND: Infantile neuronal ceroid lipofuscinosis (INCL) is an autosomal recessive disorder starting in infancy as early as 12-month-old, caused by PPT1 (palmitoyl-protein thioesterase 1) mutations, and characterized by progressive psychomotor deterioration, brain atrophy, myoclonic jerk and visual impairment. INCL can be diagnosed by brain magnetic resonance image (MRI) prior to rapid deterioration stage. To date, there is no INCL patient whose manifestation was caused by uniparental isodisomy (UPiD). PATIENT: We reported a girl diagnosed with INCL. Genetic analysis revealed a novel PPT1 mutation c.20_47del28:p.Leu7Hisfs*21. Only the father of the patient was found as a carrier of this mutation. SNP array showed the mutation became homozygous by paternal UPiD of chromosome 1. DISCUSSION: Although ICNL is a rare disease except in Finland, it is not difficult to diagnose it since the clinical symptoms and MRI findings are characteristic. Genetic testing is useful for definitive diagnosis, and distinction of UPiD is essential for genetic counseling.
Asunto(s)
Cromosomas Humanos Par 1 , Proteínas de la Membrana/genética , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/fisiopatología , Disomía Uniparental/genética , Disomía Uniparental/fisiopatología , Encéfalo/diagnóstico por imagen , Preescolar , Diagnóstico Diferencial , Femenino , Mutación del Sistema de Lectura , Humanos , Lactante , Imagen por Resonancia Magnética , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Tioléster Hidrolasas , Disomía Uniparental/diagnósticoAsunto(s)
Proteínas de la Membrana/genética , Mutación , Disomía Uniparental/genética , Vejiga Urinaria Neurogénica/etiología , Síndrome de Wolfram/genética , Fármacos Antidiuréticos/uso terapéutico , Niño , Cromosomas Humanos Par 4 , Desamino Arginina Vasopresina/uso terapéutico , Diabetes Insípida/diagnóstico , Diabetes Insípida/etiología , Salud de la Familia , Femenino , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/etiología , Homocigoto , Humanos , Hidronefrosis/etiología , Hidronefrosis/prevención & control , Madres , Resultado del Tratamiento , Disomía Uniparental/fisiopatología , Vejiga Urinaria Neurogénica/tratamiento farmacológico , Vejiga Urinaria Neurogénica/fisiopatología , Síndrome de Wolfram/fisiopatologíaRESUMEN
Limited literature exists on children and adults diagnosed with the mosaic form of trisomy 9. Data from the Tracking Rare Incidence Syndromes (TRIS) project has provided physical characteristics and medical conditions for 14 individuals. This article provides TRIS Survey results of 25 additional cases at two data points (birth and survey completion) as well as developmental status. Results confirmed a number of phenotypic features and medical conditions. In addition, a number of cardiac anomalies were reported along with feeding and respiratory difficulties in the immediate postnatal period. In addition, developmental status data indicated a range in functioning level up to skills in the 36 and 48-month range. Strengths were also noted across the sample in language and communication, fine motor and social-emotional development. Implications for professionals caring for children with this genetic condition are offered.
Asunto(s)
Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Trisomía/genética , Trisomía/fisiopatología , Disomía Uniparental/genética , Disomía Uniparental/fisiopatología , Adulto , Niño , Preescolar , Cromosomas Humanos Par 9/genética , Discapacidades del Desarrollo/diagnóstico , Femenino , Humanos , Lactante , Masculino , Mosaicismo , Fenotipo , Embarazo , Diagnóstico Prenatal , Trisomía/diagnóstico , Disomía Uniparental/diagnósticoRESUMEN
Patients with biallelic mutations for Huntington disease (HD) are rare. We present a 46-year-old female with two expanded Huntingtin (HTT) alleles with just one known affected parent. This is the first reported patient with molecular studies performed to exclude HTT uniparental disomy (UPD). The proband had biparental inheritance of HTT alleles (42/44 CAG repeats). Given the negative UPD results, the proband's unaffected mother either had a reduced penetrance allele that expanded into the full mutation range during transmission to our patient or an unknown full HTT mutation and died before symptom onset, unlikely given no family history of HD and asymptomatic at age 59. We made the novel observation in our literature review that most patients with biallelic HD did not have two full HTT mutations. Most had one HTT allele that was in the intermediate or reduced penetrance ranges or 40 CAG repeats, the lowest limit of the full mutation range. Although the number of patients is small, when an allele in these size ranges was present, generally the age of HD onset was in the 50s. If the second HTT allele had >45 repeats, then onset was typically 20s-30s. While similar ages of onset have been reported for patients with one or two HTT mutations, patients with biallelic mutations may have later onset if an expanded HTT allele has ≤40 CAG repeats. Finally, we propose that "biallelic mutations" or "compound heterozygosity" are more accurate descriptive terms than "homozygosity" when there are two non-identical expanded HTT alleles.
Asunto(s)
Alelos , Enfermedad de Huntington/genética , Proteínas del Tejido Nervioso/genética , Disomía Uniparental/genética , Femenino , Haplotipos , Heterocigoto , Homocigoto , Humanos , Proteína Huntingtina , Enfermedad de Huntington/fisiopatología , Persona de Mediana Edad , Mutación , Linaje , Penetrancia , Repeticiones de Trinucleótidos/genética , Disomía Uniparental/fisiopatologíaRESUMEN
The phenotypes associated with paternal uniparental disomy for chromosome 14 (UPD(14)pat) are clinically distinctive and caused by genetic alterations at the 14q32.2 imprinted region. Here we describe prenatal and neonatal findings in a case of epimutation associated with UPD(14)pat-like phenotype. A 25-year-old Japanese woman was referred to hospital at 32 weeks of gestation for management of threatened premature delivery. Fetal ultrasound and magnetic resonance imaging showed a narrow thorax and polyhydramnios. At 35 weeks of gestation, emergency cesarean section was performed and placentomegaly was identified. Physical examination of the neonate indicated a small narrow thorax, diastasis recti, and dysmorphic facial features that included hirsute forehead, broad flat nasal bridge, micrognathia, small ears, and a long protruding philtrum. Genetic analysis identified epimutation at the intergenic differentially methylated region (IG-DMR) and at MEG3-DMR.
Asunto(s)
Epigénesis Genética , Trabajo de Parto Prematuro/etiología , ARN Largo no Codificante/metabolismo , Disomía Uniparental/fisiopatología , Adulto , Cesárea , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 14/metabolismo , Análisis Citogenético , Metilación de ADN , ADN Intergénico , Femenino , Humanos , Recién Nacido , Japón , Masculino , Trabajo de Parto Prematuro/prevención & control , Enfermedades Placentarias/etiología , Polihidramnios/etiología , Embarazo , Nacimiento Prematuro/etiología , Ultrasonografía Prenatal , Disomía Uniparental/genéticaRESUMEN
Paternal uniparental disomy 14 (UPD(14)pat) and epimutations and microdeletions affecting the maternally derived 14q32.2 imprinted region lead to a unique constellation of clinical features such as facial abnormalities, small bell-shaped thorax with a coat-hanger appearance of the ribs, abdominal wall defects, placentomegaly, and polyhydramnios. In this study, we performed comprehensive clinical studies in patients with UPD(14)pat (n=23), epimutations (n=5), and microdeletions (n=6), and revealed several notable findings. First, a unique facial appearance with full cheeks and a protruding philtrum and distinctive chest roentgenograms with increased coat-hanger angles to the ribs constituted the pathognomonic features from infancy through childhood. Second, birth size was well preserved, with a median birth length of ±0 SD (range, -1.7 to +3.0 SD) and a median birth weight of +2.3 SD (range, +0.1 to +8.8 SD). Third, developmental delay and/or intellectual disability was invariably present, with a median developmental/intellectual quotient of 55 (range, 29-70). Fourth, hepatoblastoma was identified in three infantile patients (8.8%), and histological examination in two patients showed a poorly differentiated embryonal hepatoblastoma with focal macrotrabecular lesions and well-differentiated hepatoblastoma, respectively. These findings suggest the necessity of an adequate support for developmental delay and periodical screening for hepatoblastoma in the affected patients, and some phenotypic overlap between UPD(14)pat and related conditions and Beckwith-Wiedemann syndrome. On the basis of our previous and present studies that have made a significant contribution to the clarification of underlying (epi)genetic factors and the definition of clinical findings, we propose the name 'Kagami-Ogata syndrome' for UPD(14)pat and related conditions.