Pulmonary arterial hypertension (PAH) sometimes co-exists with hereditary hemorrhagic telangiectasia (HHT). Despite being clinically diagnosable according to Curaçao criteria, HHT can be difficult to ...diagnose due to its clinically heterogenicity and highly overlapping with PAH. Genetic analysis of the associated genes
,
,
and
can help to confirm or discard the presumptive diagnosis. As part of the clinical routine and to establish a genetic diagnosis, we have analyzed a cohort of patients with PAH and overlapping HHT features through a customized Next Generation Sequencing (NGS) panel of 21 genes, designed and validated in-house. We detected a homozygous missense variant in
in a pediatric patient diagnosed with PAH associated with HHT and a missense variant along with a heterozygous deletion in another idiopathic PAH patient (compound heterozygous inheritance). In order to establish variant segregation, we analyzed all available family members. In both cases, parents were carriers for the variants, but neither was affected. Our results expand the clinical spectrum and the inheritance pattern associated with
pathogenic variants suggesting incomplete penetrance and/or variability of expressivity with a semi-dominant pattern of inheritance.
Beckwith–Wiedemann syndrome spectrum (BWSp) is an overgrowth disorder caused by imprinting or genetic alterations at the 11p15.5 locus. Clinical features include overgrowth, macroglossia, neonatal ...hypoglycaemia, omphalocele, hemihyperplasia, cleft palate, and increased neoplasm incidence. The most common molecular defect observed is hypomethylation at the imprinting centre 2 (KCNQ1OT1:TSS DMR) in the maternal allele, which accounts for approximately 60% of cases, although CDKN1C pathogenic variants have been reported in 5–10% of patients, with a higher incidence in familial cases. In this study, we examined the clinical and molecular features of all cases of BWSp identified by the Spanish Overgrowth Registry Initiative with pathogenic or likely pathogenic CDKN1C variants, ascertained by Sanger sequencing or next-generation sequencing, with special focus on the neoplasm incidence, given that there is scarce knowledge of this feature in CDKN1C-associated BWSp. In total, we evaluated 21 cases of BWSp with CDKN1C variants; 19 were classified as classical BWS according to the BWSp scoring classification by Brioude et al. One of our patients developed a mediastinal ganglioneuroma. Our study adds evidence that tumour development in patients with BWSp and CDKN1C variants is infrequent, but it is extremely relevant to the patient’s follow-up and supports the high heterogeneity of BWSp clinical features associated with CDKN1C variants.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic hereditary renal disease, promoting end-stage renal disease (ESRD). Klinefelter syndrome (KS) is a consequence of ...an extra copy of the X chromosome in males. Main symptoms in KS include hypogonadism, tall stature, azoospermia, and a risk of cardiovascular diseases, among others. Gitelman syndrome (GS) is an autosomal recessive disorder caused by SLC12A3 variants, and is associated with hypokalemia, hypomagnesemia, hypocalciuria, normal or low blood pressure, and salt loss. The three disorders have distinct and well-delineated clinical, biochemical, and genetic findings. We here report a male patient with ADPKD who developed early chronic renal failure leading to ESRD, presenting with an intracranial aneurysm and infertility. NGS identified two de novo PKD1 variants, one known (likely pathogenic), and a previously unreported variant of uncertain significance, together with two SLC12A3 pathogenic variants. In addition, cytogenetic analysis showed a 47, XXY karyotype. We investigated the putative impact of this rare association by analyzing possible clinical, biochemical, and/or genetic interactions and by comparing the evolution of renal size and function in the proband with three age-matched ADPKD (by variants in PKD1) cohorts. We hypothesize that the coexistence of these three genetic disorders may act as modifiers with possible synergistic actions that could lead, in our patient, to a rapid ADPKD progression.
This study aimed to establish a catalog of probes corresponding to imprinted differentially methylated regions (DMRs) on the Infinium HumanMethylationEPIC BeadChip.
Reciprocal uniparental diploidies ...with low normal biparental mosaic contribution, together with normal diploid controls, were subjected to EPIC BeadChip hybridization. The methylation profiles were assessed for imprinted differential methylation. Top candidates were validated using locus-specific PCR-based assays.
Seven hundred and eighty-nine CpG probes coincided with 50 known imprinted DMRs and 467 CpG probes corresponding to 124 novel imprinted DMR candidates were identified. Validation led to identification of several subtle DMRs within known imprinted domains as well as novel maternally methylated regions associated with
and
.
Our comprehensive list of
-imprinted DMR probes will simplify and facilitate methylation profiling of individuals with imprinting disorders and is applicable to other diseases in which aberrant imprinting has been implicated, such as cancer and fetal growth.
Nuevas mutaciones asociadas a la enfermedad de Hirschsprung Lorente-Ros, Marta; Andrés, Ane Miren; Sánchez-Galán, Alba ...
Anales de pediatría (Barcelona, Spain : 2003),
October 2020, 2020-10-00, 2020-10-01, Letnik:
93, Številka:
4
Journal Article
Recenzirano
Odprti dostop
La enfermedad de Hirschsprung está causada por un defecto de la migración celular desde la cresta neural hasta el tracto gastrointestinal, resultando en la ausencia de neuronas en el plexo ...mientérico. Mutaciones en varios genes han sido asociadas a la enfermedad de Hirschsprung, la mayoría afectando a la vía del protooncogén RET. El objetivo de este estudio es la descripción de mutaciones tanto descritas como nuevas asociadas a la enfermedad de Hirschsprung, así como sus implicaciones pronósticas.
Análisis retrospectivo de pacientes con enfermedad de Hirschsprung y resultados genéticos positivos desde 1970 hasta 2013.
En la serie global, 21 pacientes tenían resultados genéticos positivos, 17 de ellos afectando la vía del protooncogén RET. Dos de las mutaciones son nuevas y no han sido previamente descritas en la literatura médica.
El protooncogén RET es el principal gen asociado a la enfermedad de Hirschsprung. Todavía hay múltiples mutaciones desconocidas relacionadas con la patogenia de la enfermedad. El estudio genético del gen RET debe formar parte del estudio diagnóstico de todos los pacientes con enfermedad de Hirschsprung, así como de sus familiares de primer grado en caso de que las mutaciones estén asociadas a los síndromes MEN2A y MEN2B.
Hirschsprung disease is caused by an impairment in cell migration from the neural crest to the gastrointestinal tract, resulting in an absence of neurons in the myenteric plexus. Many mutations in several genes have been associated to Hirschsprung disease; most of them affecting the RET proto-oncogen pathway. The purpose of this study is the description of novel and known mutations in genes associated to Hirschsprung disease and their prognostic implications.
Retrospective analysis of patients with Hirschsprung disease and positive genetic studies evaluated from 1970 to 2013.
We found 21 positive genetic studies in the global series, 17 of them involving the RET proto-oncogene. Two of the mutations are novel and they have not been reported in the medical literature.
The RET protooncogene is the main gene associated with Hirschsprung disease. There are still multiple unknown mutations related to the pathogenesis of the disease. The study of this gene must be part of the work-up of all patients with Hirschsprung disease, as well as their first degree relatives if the mutation is associated with MEN2A and MEN2B syndromes.
Somatic defects at five loci, WT1, CTNNB1, WTX, TP53 and the imprinted 11p15 region, are implicated in Wilms tumor, the commonest childhood kidney cancer. In this study we analysed all five loci in ...120 Wilms tumors. We identified epigenetic 11p15 abnormalities in 69% of tumors, 37% were H19 epimutations and 32% were paternal uniparental disomy (pUPD). We identified mutations of WTX in 32%, CTNNB1 in 15%, WT1 in 12% and TP53 in 5% of tumors. We identified several significant associations: between 11p15 and WTX (P=0.007), between WT1 and CTNNB1 (P less than 0.001), between WT1 and pUPD 11p15 (P=0.01), and a strong negative association between WT1 and H19 epimutation (P less than 0.001). We next used these data to stratify Wilms tumor into three molecular Groups, based on the status at 11p15 and WT1. Group 1 tumors (63%) were defined as 11p15-mutant and WT1-normal; a third also had WTX mutations. Group 2 tumors (13%) were WT1-mutant. They either had 11p15 pUPD or were 11p15-normal. Almost all had CTNNB1 mutations but none had H19 epimutation. Group 3 tumors (25%) were defined as 11p15-normal and WT1-normal and were typically normal at all five loci (P less than 0.001). We also identified a novel clinical association between H19 epimutation and bilateral disease (P less than 0.001). These data provide new insights into the pattern, order, interactions and clinical associations of molecular events in Wilms tumor.
SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan-Lumish ...syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin-Pappas syndrome (RAPAS). LLS MIM #616831 is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS MIM #6201551 is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in
were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 MIM 620157. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the
gene. Here we describe 18 new patients with variants in
, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in
that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with
.
Intellectual disability is a neurodevelopmental disorder in which genetic, epigenetic and environmental factors are involved. In consequence, the determination of its etiology is usually complex. ...Though many countries have migrated from conventional cytogenetic analysis to chromosomal microarrays as the first-tier genetic test for patients with this condition, this last technique was implemented in our country a few years ago. We report on the results of the implementation of chromosomal microarrays in a cohort of 133 patients with intellectual disability and dysmorphic features, normal karyotype and normal subtelomeric MLPA results in an Argentinean public health institution. Clinically relevant copy number variants were found in 12% of the patients and one or more copy number variants classified as variants of uncertain significance were found in 5.3% of them. Although the diagnostic yield of chromosomal microarrays is greater than conventional cytogenetics for these patients, there are financial limitations to adopt this technique as a first-tier test in our country, especially in the public health system.
Pulmonary arterial hypertension is a very infrequent disease, with a variable etiology and clinical expressivity, making sometimes the clinical diagnosis a challenge. Current classification based on ...clinical features does not reflect the underlying molecular profiling of these groups. The advance in massive parallel sequencing in PAH has allowed for the describing of several new causative and susceptibility genes related to PAH, improving overall patient diagnosis. In order to address the molecular diagnosis of patients with PAH we designed, validated, and routinely applied a custom panel including 21 genes. Three hundred patients from the National Spanish PAH Registry (REHAP) were included in the analysis. A custom script was developed to annotate and filter the variants. Variant classification was performed according to the ACMG guidelines. Pathogenic and likely pathogenic variants have been found in 15% of the patients with 12% of variants of unknown significance (VUS). We have found variants in patients with connective tissue disease (CTD) and congenital heart disease (CHD). In addition, in a small proportion of patients (1.75%), we observed a possible digenic mode of inheritance. These results stand out the importance of the genetic testing of patients with associated forms of PAH (i.e., CHD and CTD) additionally to the classical IPAH and HPAH forms. Molecular confirmation of the clinical presumptive diagnosis is required in cases with a high clinical overlapping to carry out proper management and follow up of the individuals with the disease.
Pulmonary arterial hypertension (PAH) is an infrequent disorder characterized by high blood pressure in the pulmonary arteries. It may lead to premature death or the requirement for lung and/or heart ...transplantation. Genetics plays an important and increasing role in the diagnosis of PAH. Here, we report seven additional patients with variants in
and a review of sixty previously described patients in the literature. Patients described in this study suffered with additional conditions including large septal defects, as described by other groups. Collectively, sixty-seven PAH patients have been reported so far with variants in
, including missense and loss-of-function (LoF) variants. The majority of the loss-of-function variants found in
were detected in the last exon of the gene. Meanwhile, most missense variants were located within exon one, suggesting a probable tolerated change at the amino terminal part of the protein. In addition, we reported two idiopathic PAH patients presenting with the same variant previously detected in five patients by other studies, suggesting a possible hot spot. Research conducted on PAH associated with congenital heart disease (CHD) indicated that variants in
might be particularly prevalent in this subgroup, as two out of our seven additional patients presented with CHD. Further research is still necessary to clarify the precise association between the biological pathway of
and the development of PAH.
PDF
