RESUMEN
OBJECTIVES: To determine the incremental yield of prenatal exome sequencing (PES) over standard testing in fetuses with an isolated congenital heart abnormality (CHA), CHA associated with extra-cardiac malformations (ECMs) and CHA dependent upon anatomical subclassification. METHODS: A systematic review of the literature was performed using MEDLINE, EMBASE, Web of Science and grey literature January 2010-February 2023. Studies were selected if they included greater than 20 cases of prenatally diagnosed CHA when standard testing (QF-PCR/chromosome microarray/karyotype) was negative. Pooled incremental yield was determined. PROSPERO CRD 42022364747. RESULTS: Overall, 21 studies, incorporating 1957 cases were included. The incremental yield of PES (causative pathogenic and likely pathogenic variants) over standard testing was 17.4% (95% CI, 13.5%-21.6%), 9.3% (95% CI, 6.6%-12.3%) and 35.9% (95% CI, 21.0%-52.3%) for all CHAs, isolated CHAs and CHAs associated with ECMs. The subgroup with the greatest yield was complex lesions/heterotaxy; 35.2% (95% CI 9.7%-65.3%). The most common syndrome was Kabuki syndrome (31/256, 12.1%) and most pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease causing genes (114/224, 50.9%). CONCLUSION: The likelihood of a monogenic aetiology in fetuses with multi-system CHAs is high. Clinicians must consider the clinical utility of offering PES in selected isolated cardiac lesions.
Asunto(s)
Secuenciación del Exoma , Cardiopatías Congénitas , Diagnóstico Prenatal , Humanos , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/diagnóstico , Femenino , Embarazo , Secuenciación del Exoma/métodos , Diagnóstico Prenatal/métodosAsunto(s)
Neoplasias del Sistema Nervioso Central , Neoplasias de Células Germinales y Embrionarias , Niño , Humanos , Metilación de ADN , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Neoplasias de Células Germinales y Embrionarias/genética , Sistema Nervioso Central/patologíaRESUMEN
Congenital lipomatous overgrowth with vascular, epidermal, and skeletal (CLOVES) anomalies and Klippel-Trenaunay (KTS) syndromes are caused by somatic gain-of-function mutations in PIK3CA, encoding a catalytic subunit of phosphoinositide 3-kinase. Affected tissue is needed to find mutations, as mutant alleles are not detectable in blood. Because some patients with CLOVES develop Wilms tumor, we tested urine as a source of DNA for mutation detection. We extracted DNA from the urine of 17 and 24 individuals with CLOVES and KTS, respectively, and screened 5 common PIK3CA mutation hotspots using droplet digital polymerase chain reaction. Six of 17 CLOVES participants (35%) had mutant PIK3CA alleles in urine. Among 8 individuals in whom a mutation had been previously identified in affected tissue, 4 had the same mutant allele in the urine. One study participant with CLOVES had been treated for Wilms tumor. We detected the same PIK3CA mutation in her affected tissue, urine, and tumor, indicating Wilms tumors probably arise from PIK3CA mutant cells in patients with CLOVES. No urine sample from a participant with KTS had detectable PIK3CA mutations. We suggest that urine, which has the advantage of being collected non-invasively, is useful when searching for mutations in individuals with CLOVES syndrome.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/genética , Síndrome de Klippel-Trenaunay-Weber/genética , Lipoma/genética , Anomalías Musculoesqueléticas/genética , Nevo/genética , Malformaciones Vasculares/genética , Tumor de Wilms/genética , Adolescente , Adulto , Alelos , Niño , Preescolar , ADN/genética , ADN/orina , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Síndrome de Klippel-Trenaunay-Weber/patología , Síndrome de Klippel-Trenaunay-Weber/orina , Lipoma/patología , Lipoma/orina , Masculino , Persona de Mediana Edad , Anomalías Musculoesqueléticas/patología , Anomalías Musculoesqueléticas/orina , Mutación , Nevo/patología , Nevo/orina , Fenotipo , Malformaciones Vasculares/patología , Malformaciones Vasculares/orina , Tumor de Wilms/patología , Tumor de Wilms/orinaRESUMEN
Okur-Chung syndrome is a neurodevelopmental condition attributed to germline CSNK2A1 pathogenic missense variants. We present 8 unreported subjects with the above syndrome, who have recognizable dysmorphism, varying degrees of developmental delay and multisystem involvement. Together with 6 previously reported cases, we present a case series of 7 female and 7 male subjects, highlighting the recognizable facial features of the syndrome (microcephaly, hypertelorism, epicanthic fold, ptosis, arched eyebrows, low set ears, ear fold abnormality, broad nasal bridge and round face) as well as frequently occurring clinical features including neurodevelopmental delay (93%), gastrointestinal (57%), musculoskeletal (57%) and immunological (43%) abnormalities. The variants reported in this study are evolutionary conserved and absent in the normal population. We observed that the CSNK2A1 gene is relatively intolerant to missense genetic changes, and most variants are within the protein kinase domain. All except 1 variant reported in this cohort are spatially located on the binding pocket of the holoenzyme. We further provide key recommendations on the management of Okur-Chung syndrome. To conclude, this is the second case series on Okur-Chung syndrome, and an in-depth review of the phenotypic features and genomic findings of the condition with suggestions on clinical management.
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Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Adolescente , Quinasa de la Caseína II/química , Quinasa de la Caseína II/genética , Niño , Preescolar , Discapacidades del Desarrollo/fisiopatología , Cara/fisiopatología , Femenino , Genotipo , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Anomalías Musculoesqueléticas/genética , Anomalías Musculoesqueléticas/fisiopatología , Mutación Missense/genética , Trastornos del Neurodesarrollo/fisiopatología , Fenotipo , Conformación Proteica , Pliegue de Proteína , Secuenciación del Exoma/métodosRESUMEN
SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction (IUGR) <10th percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.
RESUMEN
Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1(+/-)-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1(+/-) signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing.
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Metilación de ADN/genética , Genoma Humano , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Nucleares/metabolismo , Síndrome de Sotos/genética , Regulación de la Expresión Génica , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Proteínas Nucleares/genéticaRESUMEN
Klebsiella infection has previously been reported in a few patients with transfusion-dependent thalassemia. The incidence and clinical spectrum of this infection in our cohort of patients were reviewed retrospectively. Among 160 patients observed for 12 years, there were 15 episodes of Klebsiella infection that occurred in 12 patients (7.5%), resulting in an incidence of 0.78 infections per 100 patient-years. The clinical spectrum included sinusitis (4 cases), intracranial infection (5 cases), septicemia (4 cases), and abscesses of the liver, lung, kidney, and parotid gland (1 case each). Three patients had recurrent infections involving different sites, 2 (16%) died of fulminant septicemia, and 3 (25%) had significant permanent neurological deficits. The antibiotic susceptibility pattern for the isolates was similar to the pattern for isolates recovered in the community. With regard to predisposing factors, iron overload and liver function derangement were found to be significant on univariate analysis (P=.046 and P=.049, respectively) but insignificant on multivariate analysis. Klebsiella infection was a serious and frequently encountered complication in our patients with transfusion-dependent thalassemia, resulting in high mortality and morbidity rates.
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Infecciones por Klebsiella/complicaciones , Talasemia/complicaciones , Adolescente , Adulto , Antibacterianos/uso terapéutico , Niño , Estudios de Cohortes , Femenino , Humanos , Incidencia , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/epidemiología , Klebsiella pneumoniae/efectos de los fármacos , Masculino , Pruebas de Sensibilidad Microbiana , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
OBJECTIVE: To delineate the clinical behaviour of chronic benign neutropenia in Chinese children in Hong Kong. DESIGN: Retrospective study. SETTING: University teaching hospital, Hong Kong. PATIENTS: All infants and children with absolute neutrophil count of 1.5 x 10(9) /L or lower for more than 3 months. MAIN OUTCOME MEASURES: Development of significant infection, and achievement of remission. RESULTS: Twenty-four children with chronic benign neutropenia were identified between 1992 and 2001. Their median age of diagnosis was 9 months. The mean (standard deviation) initial absolute neutrophil count was 0.28 x 10(9) /L (0.24 x 10(9) /L). Twenty-three patients presented with infection. Of the 19 patients tested, four (21%) were positive for anti-neutrophil antibodies. Bone marrow examination was performed in 17 patients: nine had normal results, but six showed evidence of peripheral consumption, one showed late maturation arrest at band stage, and one showed phagocytosis of myeloid cells by histiocytes. The overall hospitalised infection rate was 51.6 episodes per 1000 patient-months. Ten percent of cases were considered 'significant' infections and required hospital admission with either surgical intervention or intravenous therapy (antibiotics or fluid replacement). In the first year of diagnosis, more than 80% of patients had their lowest absolute neutrophil count (mean, 0.16 x 10(9) /L; standard deviation, 0.11 x 10(9) /L). Granulocyte-colony stimulating factor was used to treat three patients and induced transient elevation of absolute neutrophil count in all three. The projected remission rate was 55.4% at 3 years. Even for those with persistent disease, there was significant recovery in absolute neutrophil count to a mean of 0.5 x 10(9) /L (P<0.01). CONCLUSIONS: Patients with chronic benign neutropenia experienced a relatively benign clinical course regardless of their remission status. Only a small proportion of patients developed significant infections. A multi-centre prospective study may help identify predictive factors of remission.