Background:
The etiology, course, and most appropriate management of borderline congenital hypothyroidism (CH) are poorly defined, such that the optimal threshold for diagnosis with bloodspot ...screening thyrotropin (bsTSH) measurement remains controversial. Dual oxidase 2 (
DUOX2
) mutations may initially cause borderline elevation of bsTSH, which later evolves into significant hypothyroidism on venous blood measurement. It was hypothesized that mutations in both
DUOX2
and its accessory protein
DUOXA2
may occur frequently, even in patients with borderline bsTSH elevation, such that higher diagnostic thresholds in bsTSH screening may fail to detect such cases, with consequent risk of undiagnosed neonatal hypothyroidism of sufficient magnitude to require thyroxine therapy. This study aimed to investigate the frequency and characteristics of
DUOX2
and
DUOXA2
mutations in a borderline CH cohort.
Methods:
A cross-sectional study of patients with borderline CH was undertaken at Great Ormond Street Hospital, a tertiary British pediatric center.
DUOX2
was sequenced in 52 patients with a bsTSH of 6–19.9 mIU/L, venous TSH of >25 mIU/L, and eutopic thyroid gland
in situ
.
DUOXA2
was sequenced in
DUOX2
mutation-negative cases, and novel
DUOXA2
mutations were functionally characterized.
Results:
A total of 26 (50%) patients harbored likely pathogenic mutations in
DUOX2
(
n
= 20; 38%) or
DUOXA2
(
n
= 6; 12%), including novel gene variants (
DUOX2
,
n
= 3;
DUOXA2
,
n
= 7). Two recurrent
DUOX2
mutations (p.Q570L, p.F966Sfs*29) occurred frequently in population databases (MAF ≥0.01). Despite bsTSH being <10 mIU/L in 46% of
DUOX2
and
DUOXA2
mutation-positive cases, venous free thyroxine levels in these patients were in the moderate CH range (
M
= 9.3 pmol/L, range <3.9–15.8 pmol/L),
Conclusions:
Targeted
DUOX2
and
DUOXA2
sequencing in a borderline CH cohort has a high diagnostic yield. These findings might argue for a lowering of bsTSH thresholds, but follow-up studies are required to assess whether cases with borderline bsTSH harboring
DUOX2
/
DUOXA2
mutations will benefit from an early diagnosis and subsequent levothyroxine treatment.
Objective
To describe the clinical findings in patients with incidental prostatic amyloidosis.
Patients and methods
Retrospective search in the database of the Department of Pathology, Hospital de ...Bellvitge, for prostate specimens with amyloid. Congo red and immunohistochemical staining of the sections. Review of the patients’ clinical charts for symptoms attributable to systemic amyloidosis.
Results
Amyloid deposition in the prostate was identified and reported in 40 patients between 2001 and 2022. Median age was 76.5 years (range = 62–90 years). Prostate cancer was diagnosed in 25 patients. Only four patients had a previous diagnosis of amyloidosis. In the remaining 36 the prostate sample (31 needle biopsies, two transurethral resections (TUR), two simple prostatectomies, one radical cystectomy for bladder cancer) provided the initial diagnosis. Amyloid deposits were mainly located in the wall of small vessels and rarely in the prostatic stroma. Immunohistochemistry was available in 32 cases, 26 of which were positive for TTR. All patients showed at least one symptom indicative of systemic amyloidosis, the most frequent being hearing loss (55%), carpal tunnel syndrome (42,5%) or other osteoarticular symptoms (tendinopathies, osteoarthritis), cataracts (37.5%) and cardiac symptoms (32.5%), among others.
Conclusion
The prostate is a target tissue for amyloid deposition. The incidental finding of amyloid in prostate corresponds, in the majority of cases, to previously undiagnosed systemic TTR amyloidosis in patients lacking signs of heart involvement but having mainly osteoarticular symptoms, hearing and visual impairment.
Context:
Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known ...dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken.
Objective:
Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS.
Patients, Design, and Setting:
We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico.
Results:
Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases.
Conclusions:
The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.
TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD and TSHR genes were screened in 49 cases of congenital hypothyroidism with eutopic gland-in-situ. 59% were solved including cases with triallelic mutations.
We identified four different missense mutations in the single-exon gene MAB21L2 in eight individuals with bilateral eye malformations from five unrelated families via three independent exome ...sequencing projects. Three mutational events altered the same amino acid (Arg51), and two were identical de novo mutations (c.151C>T p.Arg51Cys) in unrelated children with bilateral anophthalmia, intellectual disability, and rhizomelic skeletal dysplasia. c.152G>A (p.Arg51His) segregated with autosomal-dominant bilateral colobomatous microphthalmia in a large multiplex family. The fourth heterozygous mutation (c.145G>A p.Glu49Lys) affected an amino acid within two residues of Arg51 in an adult male with bilateral colobomata. In a fifth family, a homozygous mutation (c.740G>A p.Arg247Gln) altering a different region of the protein was identified in two male siblings with bilateral retinal colobomata. In mouse embryos, Mab21l2 showed strong expression in the developing eye, pharyngeal arches, and limb bud. As predicted by structural homology, wild-type MAB21L2 bound single-stranded RNA, whereas this activity was lost in all altered forms of the protein. MAB21L2 had no detectable nucleotidyltransferase activity in vitro, and its function remains unknown. Induced expression of wild-type MAB21L2 in human embryonic kidney 293 cells increased phospho-ERK (pERK1/2) signaling. Compared to the wild-type and p.Arg247Gln proteins, the proteins with the Glu49 and Arg51 variants had increased stability. Abnormal persistence of pERK1/2 signaling in MAB21L2-expressing cells during development is a plausible pathogenic mechanism for the heterozygous mutations. The phenotype associated with the homozygous mutation might be a consequence of complete loss of MAB21L2 RNA binding, although the cellular function of this interaction remains unknown.
To further resolve the genetic architecture of the inflammatory bowel diseases ulcerative colitis and Crohn's disease, we sequenced the whole genomes of 4,280 patients at low coverage and compared ...them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing genome-wide association study cohorts and tested for association at ∼12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles the risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn's disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve understanding of the biology of complex diseases.
Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families ...with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7-null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation. SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear.
Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational ...approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The evaluation of the energy yield (EY) in Photovoltaic (PV) systems depends strongly on the quality of the onsite irradiance measurement. Prior to system installation, normally only the horizontal ...plane irradiance is available and therefore various mathematical models are used to translate the measured values into the plane of the PV array. This paper evaluates the influence of irradiance models, and specifically diffuse tilted irradiance models, on the accuracy of the EY calculation. For this purpose several PV installations were evaluated by comparing measured global tilted irradiance values and measured DC energy with modeled values.
Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide ...genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10
), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10
). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.
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