RESUMEN
HDR syndrome is a rare disease characterized by hypoparathyroidism, deafness, and renal dysplasia. An autosomal dominant disease caused by heterozygous pathogenic GATA3 variants, the penetrance of each associated condition is variable. Literature reviews have provided some answers, but many questions remain, in particular what the relationship is between genotype and phenotype. The current study examines 28 patients with HDR syndrome combined with an exhaustive review of the literature. Some conditions such as hearing loss are almost always present, while others described as rare initially, do not seem to be so rare after all (genital malformations and basal ganglia calcifications). By modeling pathogenic GATA3 variants found in HDR syndrome, we found that missense variations appear to always be located in the same area (close to the two Zinc Finger domain). We describe new pathogenic GATA3 variants, of which some seem to always be associated with certain conditions. Many audiograms were studied to establish a typical audiometric profile associated with a phenotype in HDR. As mentioned in the literature, hearing function should always be assessed as early as possible and follow up of patients with HDR syndrome should include monitoring of parathyroid function and vesicoureteral reflux in order to prevent complications.
Asunto(s)
Factor de Transcripción GATA3 , Hipoparatiroidismo , Fenotipo , Humanos , Hipoparatiroidismo/genética , Hipoparatiroidismo/patología , Factor de Transcripción GATA3/genética , Masculino , Femenino , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/patología , Estudios de Asociación Genética , Nefrosis/genética , Nefrosis/patología , Niño , Predisposición Genética a la Enfermedad , Mutación , Preescolar , Estudios de CohortesRESUMEN
The SMARCC1 gene has been involved in congenital ventriculomegaly with aqueduct stenosis but only a few patients have been reported so far, with no antenatal cases, and it is currently not annotated as a morbid gene in OMIM nor in the Human Phenotype Ontology. Most of the reported variants are loss of function (LoF) and are often inherited from unaffected parents. SMARCC1 encodes a subunit of the mSWI/SNF complex and affects the chromatin structure and expression of several genes. Here, we report the two first antenatal cases of SMARCC1 LoF variants detected by Whole Genome Sequencing (WGS). Ventriculomegaly is the common feature in those fetuses. Both identified variants are inherited from a healthy parent, which supports the reported incomplete penetrance of this gene. This makes the identification of this condition in WGS as well as the genetic counseling challenging.
Asunto(s)
Hidrocefalia , Humanos , Hidrocefalia/diagnóstico por imagen , Hidrocefalia/genética , Feto , Asesoramiento Genético , Factores de Transcripción/genéticaRESUMEN
Smith-Magenis syndrome (SMS), characterized by dysmorphic features, neurodevelopmental disorder, and sleep disturbance, is due to an interstitial deletion of chromosome 17p11.2 (90%) or to point mutations in the RAI1 gene. In this retrospective cohort, we studied the clinical, cognitive, and behavioral profile of 47 European patients with SMS caused by a 17p11.2 deletion. We update the clinical and neurobehavioral profile of SMS. Intrauterine growth was normal in most patients. Prenatal anomalies were reported in 15%. 60% of our patients older than 10 years were overweight. Prevalence of heart defects (6.5% tetralogy of Fallot, 6.5% pulmonary stenosis), ophthalmological problems (89%), scoliosis (43%), or deafness (32%) were consistent with previous reports. Epilepsy was uncommon (2%). We identified a high prevalence of obstipation (45%). All patients had learning difficulties and developmental delay, but ID range was wide and 10% of patients had IQ in the normal range. Behavioral problems included temper tantrums and other difficult behaviors (84%) and night-time awakenings (86%). Optimal care of SMS children is multidisciplinary and requires important parental involvement. In our series, half of patients were able to follow adapted schooling, but 70% of parents had to adapt their working time, illustrating the medical, social, educative, and familial impact of having a child with SMS.
Asunto(s)
Síndrome de Smith-Magenis/epidemiología , Anomalías Múltiples/genética , Adolescente , Niño , Trastornos de la Conducta Infantil/genética , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 17/ultraestructura , Discapacidades del Desarrollo/genética , Educación Especial , Relaciones Familiares , Trastornos del Crecimiento/genética , Humanos , Discapacidad Intelectual/genética , Sobrepeso/genética , Padres , Aceptación de la Atención de Salud/estadística & datos numéricos , Fenotipo , Diagnóstico Prenatal , Estudios Retrospectivos , Trastornos del Sueño-Vigilia/genética , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/embriología , Síndrome de Smith-Magenis/psicología , Adulto JovenRESUMEN
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease of motile cilia. Even though PCD is widely studied, North-African patients have been rarely explored. In this study, we aim at confirming the clinical diagnosis and explore the genetic spectrum of PCD in a cohort of Tunisian patients. Forty clinically diagnosed patients with PCD belonging to 34 families were recruited from Tunisian pediatric departments. In each proband, targeted capture PCD panel sequencing of the 40 PCD genes was performed. PCD panel sequencing identified bi-allelic mutations in 82% of the families in eight PCD genes. Remarkably, 23.5% of patients carried the same c.2190del CCDC39 mutation. Single nucleotide polymorphism profiling in six unrelated patients carrying this mutation has revealed a founder effect in North-African patients. This mutation is estimated to date back at least 1,400-1,750 years ago. The identification of this major allele allowed us to suggest a cost-effective genetic diagnostic strategy in North-African patients with PCD.
