scholarly journals Genetic and Phenotypic Characteristics of Congenital Hypothyroidism in a Chinese Cohort

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Long ◽  
Fang Guo ◽  
Ruen Yao ◽  
Ying Wang ◽  
Huaiyan Wang ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Single Gene ◽  
Phenotypic Characteristics ◽  
Phenotype Correlation ◽  
Gene Group ◽  
Whole Exome ◽  
Chinese Cohort ◽  
Group A ◽  
Molecular Etiology

BackgroundThe molecular etiology and the genotype–phenotype correlation of congenital hypothyroidism (CH) remain unclear.MethodsWe performed genetic analysis in 42 newborns with CH using whole-exome sequencing. Patients were divided into a single-gene group and a multi-gene group according to the number of affected genes, or divided into a monoallelic group, a biallelic group, and an oligogenic group according to the pattern of the detected variants. The clinical characteristics were compared between groups.ResultsThyroid dysgenesis (TD) was observed in 10 patients and goiter in 5 patients, whereas 27 patients had normal-sized gland-in-situ (GIS). We identified 58 variants in five genes in 29 patients. The genes with the most frequent variants were DUOX2 (70.7%), followed by TSHR (12.1%), DUOXA2 (10.3%), and TPO (5.2%). Variants in the genes causing dyshormonogenesis (DH) were more common than those in the genes causing TD (87.9% versus 12.1%). Among the patients with detected variants, 26 (89.7%) were harboring a single gene variant (single-gene group), which include 22 patients harboring biallelic variants (biallelic group) and four patients harboring monoallelic variants (monoallelic group). Three (10.3%) patients harbored variants in two or three genes (multi-gene group or oligogenic group). Compared with the single-gene group, the levothyroxine (L-T4) dose at 1 year of age was higher in the multi-gene group (p = 0.018). A controllable reduction in the L-T4 dose was observed in 25% of patients in the monoallelic group and 59.1% of patients in the biallelic group; however, no patients with such reduction in the L-T4 dose were observed in the oligogenic group.ConclusionsPatients with normal-sized GIS accounted for the majority of our cohort. Genetic defects in the genes causing DH were more common than those in the genes causing TD, with biallelic variants in DUOX2 being dominant. DH might be the leading pathophysiology of CH in Chinese individuals.

scholarly journals The mutational burden and oligogenic inheritance in Klippel-Feil Syndrome

2020 ◽  
Author(s):  
Ziquan Li ◽  
Sen Zhao ◽  
Siyi Cai ◽  
Yuanqiang Zhang ◽  
Lianlei Wang ◽  
...  
Keyword(s):  
Rare Variants ◽  
Cervical Vertebrae ◽  
Clinical Manifestations ◽  
Mutational Burden ◽  
Whole Exome ◽  
Uncertain Significance ◽  
Chinese Cohort ◽  
Oligogenic Inheritance ◽  
Molecular Etiology ◽  
Genetic Burden

Abstract Background: Klippel-Feil syndrome (KFS) represents a rare anomaly characterized by congenital fusion of cervical vertebrae. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. Methods: We consecutively recruited a Chinese cohort of 37 patients with KFS. The clinical manifestations and radiological assessments were analyzed and whole-exome sequencing (WES) was performed. Additionally, rare variants in KFS cases and controls were compared using genetic burden analysis. Results: We primarily examined rare variants in five reported genes (GDF6, MEOX1, GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of uncertain significance in MYO18B. Based on rare variant burden analysis of 96 candidate genes related to vertebral segmentation defects, we identified BAZ1B as having the highest probability of association with KFS, followed by FREM2, SUFU, VANGL1 and KMT2D. In addition, seven patients were proposed to show potential oligogenic inheritance involving more than one candidate gene, the frequency of which was significantly higher than that in the in-house controls. Conclusions: Our study presents an exome-sequenced cohort and identifies five novel genes potentially associated with KFS, extending the spectrum of known mutations contributing to this syndrome. Furthermore, the genetic burden analysis provides further evidence for potential oligogenic inheritance of KFS.

Infants Diagnosed with Athyreosis on Scintigraphy May Have a Gland Present on Ultrasound and Have Transient Congenital Hypothyroidism

2021 ◽  
pp. 1-8
Author(s):  
Niamh McGrath ◽  
Colin Patrick Hawkes ◽  
Stephanie Ryan ◽  
Philip Mayne ◽  
Nuala Murphy
Keyword(s):  
Thyroid Gland ◽  
Congenital Hypothyroidism ◽  
Thyroid Tissue ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Ultrasound ◽  
Free T4 ◽  
Median Serum ◽  
Thyroid Glands ◽  
Rule Out

Scintigraphy using technetium-99m (<sup>99m</sup>Tc) is the gold standard for imaging the thyroid gland in infants with congenital hypothyroidism (CHT) and is the most reliable method of diagnosing an ectopic thyroid gland. One of the limitations of scintigraphy is the possibility that no uptake is detected despite the presence of thyroid tissue, leading to the spurious diagnosis of athyreosis. Thyroid ultrasound is a useful adjunct to detect thyroid tissue in the absence of <sup>99m</sup>Tc uptake. <b><i>Aims:</i></b> We aimed to describe the incidence of sonographically detectable in situ thyroid glands in infants scintigraphically diagnosed with athyreosis using <sup>99m</sup>Tc and to describe the clinical characteristics and natural history in these infants. <b><i>Methods:</i></b> The newborn screening records of all infants diagnosed with CHT between 2007 and 2016 were reviewed. Those diagnosed with CHT and athyreosis confirmed on scintigraphy were invited to attend a thyroid ultrasound. <b><i>Results:</i></b> Of the 488 infants diagnosed with CHT during the study period, 18/73 (24.6%) infants with absent uptake on scintigraphy had thyroid tissue visualised on ultrasound (3 hypoplastic thyroid glands and 15 eutopic glands). The median serum thyroid-stimulating hormone (TSH) concentration at diagnosis was significantly lower than that in infants with confirmed athyreosis (no gland on ultrasound and no uptake on scintigraphy) (74 vs. 270 mU/L), and median free T4 concentration at diagnosis was higher (11.9 vs. 3.9 pmol/L). Six of 10 (60%) infants with no uptake on scintigraphy but a eutopic gland on ultrasound had transient CHT. <b><i>Conclusion:</i></b> Absent uptake on scintigraphy in infants with CHT does not rule out a eutopic gland, especially in infants with less elevated TSH concentrations. Clinically, adding thyroid ultrasound to the diagnostic evaluation of infants who have athyreosis on scintigraphy may avoid committing some infants with presumed athyreosis to lifelong levothyroxine treatment.

scholarly journals Patterns of invasive recurrence among patients originally treated for ductal carcinoma in situ by breast-conserving surgery versus mastectomy

2021 ◽  
Vol 186 (3) ◽  
pp. 617-624
Author(s):  
Kate R. Pawloski ◽  
Audree B. Tadros ◽  
Varadan Sevilimedu ◽  
Ashley Newman ◽  
Lori Gentile ◽  
...  
Keyword(s):  
Ductal Carcinoma In Situ ◽  
Carcinoma In Situ ◽  
Ductal Carcinoma ◽  
Advanced Disease ◽  
Breast Conserving Surgery ◽  
Risk Profile ◽  
High Grade ◽  
Group A ◽  
First Recurrence

Abstract Purpose Local recurrence after treatment of ductal carcinoma in situ (DCIS) with breast-conserving surgery (BCS) is more common than after mastectomy, but it is unclear if patterns of invasive recurrence vary by initial surgical therapy. Among patients with invasive recurrence after treatment for DCIS, we compared patterns of first recurrence between those originally treated with BCS vs. mastectomy. Methods From 2000 to 2016, women with an invasive recurrence occurring ≥ 6 months after initial treatment for DCIS were retrospectively identified. Clinicopathologic features and adjuvant treatment of the initial DCIS, as well as characteristics of first invasive recurrences, were compared between patients who had undergone BCS vs. mastectomy. Results 452 patients with an invasive recurrence after surgery for DCIS were identified: 367 patients (81%) had initially undergone BCS and 85 patients (19%) mastectomy. Patients originally treated with mastectomy were younger and were more likely to have had high grade, necrosis, and multifocal or multicentric DCIS (p < 0.001) compared with the BCS group. A higher proportion of invasive recurrences were local after BCS (93%; 343/367), whereas 88% (75/85) of recurrences after mastectomy were regional or distant (p < 0.001). The median time to first invasive recurrence was not different between surgical groups (BCS: 6.4 years vs. mastectomy: 5.5 years; p = 0.12). Conclusions Among women who experienced a first invasive recurrence after treatment for DCIS, those who had originally undergone mastectomy more commonly presented with advanced disease compared to those treated with BCS, likely related to the absence of the breast and the higher risk profile of their initial DCIS.

Whole exome sequencing reveals BAP1 somatic abnormalities in mesothelioma in situ

Lung Cancer ◽  
2020 ◽  
Vol 149 ◽  
pp. 1-4
Author(s):  
Sanja Dacic ◽  
Somak Roy ◽  
Maureen A. Lyons ◽  
Jan H. von der Thusen ◽  
Francoise Galateau-Salle ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Whole Exome

scholarly journals Photopolymerizable Injectable Cartilage Mimetic Hydrogel for the Treatment of Focal Chondral Lesions: A Proof of Concept Study in a Rabbit Animal Model

2018 ◽  
Vol 47 (1) ◽  
pp. 212-221 ◽  
Author(s):  
Cecilia Pascual-Garrido ◽  
Elizabeth A. Aisenbrey ◽  
Francisco Rodriguez-Fontan ◽  
Karin A. Payne ◽  
Stephanie J. Bryant ◽  
...  
Keyword(s):  
Animal Model ◽  
Chondrogenic Differentiation ◽  
Osteochondral Lesions ◽  
Chondral Defect ◽  
Group A ◽  
Group B ◽  
Safranin O

Background: In this study, we investigate the in vitro and in vivo chondrogenic capacity of a novel photopolymerizable cartilage mimetic hydrogel, enhanced with extracellular matrix analogs, for cartilage regeneration. Purpose: To (1) determine whether mesenchymal stem cells (MSCs) embedded in a novel cartilage mimetic hydrogel support in vitro chondrogenesis, (2) demonstrate that the proposed hydrogel can be delivered in situ in a critical chondral defect in a rabbit model, and (3) determine whether the hydrogel with or without MSCs supports in vivo chondrogenesis in a critical chondral defect. Study Design: Controlled laboratory study. Methods: Rabbit bone marrow–derived MSCs were isolated, expanded, encapsulated in the hydrogel, and cultured in chondrogenic differentiation medium for 9 weeks. Compressive modulus was evaluated at day 1 and at weeks 3, 6, and 9. Chondrogenic differentiation was investigated via quantitative polymerase reaction, safranin-O staining, and immunofluorescence. In vivo, a 3 mm–wide × 2-mm-deep chondral defect was created bilaterally on the knee trochlea of 10 rabbits. Each animal had 1 defect randomly assigned to be treated with hydrogel with or without MSCs, and the contralateral knee was left untreated. Hence, each rabbit served as its own matched control. Three groups were established: group A, hydrogel (n = 5); group B, hydrogel with MSCs (n = 5); and group C, control (n = 10). Repair tissue was evaluated at 6 months after intervention. Results: In vitro, chondrogenesis and the degradable behavior of the hydrogel by MSCs were confirmed. In vivo, the hydrogel could be delivered intraoperatively in a sterile manner. Overall, the hydrogel group had the highest scores on the modified O’Driscoll scoring system (group A, 17.4 ± 4.7; group B, 13 ± 3; group C, 16.7 ± 2.9) ( P = .11) and showed higher safranin-O staining (group A, 49.4% ± 20%; group B, 25.8% ± 16.4%; group C, 36.9% ± 25.2%) ( P = .27), although significance was not detected for either parameter. Conclusion: This study provides the first evidence of the ability to photopolymerize this novel hydrogel in situ and assess its ability to provide chondrogenic cues for cartilage repair in a small animal model. In vitro chondrogenesis was evident when MSCs were encapsulated in the hydrogel. Clinical Relevance: Cartilage mimetic hydrogel may offer a tissue engineering approach for the treatment of osteochondral lesions.

scholarly journals Whole-exome sequencing associates novel CSMD1 gene mutations with familial Parkinson disease

2017 ◽  
Vol 3 (5) ◽  
pp. e177 ◽  
Author(s):  
Javier Ruiz-Martínez ◽  
Luis J. Azcona ◽  
Alberto Bergareche ◽  
Jose F. Martí-Massó ◽  
Coro Paisán-Ruiz
Keyword(s):  
Parkinson Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genome Wide Association Study ◽  
Single Gene ◽  
Gene Mutations ◽  
Complement Control Protein ◽  
Genome Wide ◽  
Whole Exome ◽  
A Genome

Objective:Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases.Methods:In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole-exome sequencing analyses in affected individuals for disease gene identification.Results:Patients were diagnosed with typical PD without relevant distinctive symptoms. Two different novel mutations were identified in the CSMD1 gene. The CSMD1 gene, which encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing CNS, was previously shown to be associated with the risk of PD in a genome-wide association study.Conclusions:We conclude that the CSMD1 mutations identified in this study might be responsible for the PD phenotype observed in our examined patients. This, along with previous reported studies, may suggest the complement pathway as an important therapeutic target for PD and other neurodegenerative diseases.

scholarly journals In congenital hypothyroidism bone maturation at birth may be a predictive factor of psychomotor development during the first Year of life irrespective of other variables related to treatment

2003 ◽  
pp. 1-6 ◽  
Author(s):  
M Wasniewska ◽  
F De Luca ◽  
A Cassio ◽  
N Oggiaro ◽  
P Gianino ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Psychomotor Development ◽  
First Year ◽  
X Rays ◽  
Bone Maturation ◽  
Gestation Age ◽  
Group A ◽  
One Year ◽  
First Year Of Life ◽  
Tsh Levels

OBJECTIVE: To evaluate in a cohort of infants with congenital hypothyroidism (CH): (a) the frequency of bone maturation (BM) retardation at birth and (b) whether BM delay at birth may be considered as a tool to make a prognosis of psychomotor status at the age of 1 Year, irrespective of other variables related to treatment. DESIGN: BM at birth, CH severity and developmental quotient (DQ) at the age of 1 Year were retrospectively evaluated in 192 CH infants selected by the following inclusion criteria: (a) gestation age ranging between 38 and 42 weeks; (b) onset of therapy within the first Month of life; (c) initial thyroxine (l-T(4)) dosage ranging from 10 to 12 microg/kg/day; (d) normalization of serum thyrotropin (TSH) levels before the age of 3 Months; (e) Monthly adjustments of l-T(4) dose during the first Year of life with serum TSH levels ranging from 0.5 to 4 mIU/l; (f) no major diseases and/or physical handicaps associated with CH; (g) availability of both thyroid scanning and knee X-rays at the time of treatment initiation; (h) availability of DQ assessment at an average age of 12 Months. METHODS: BM was considered normal if the distal femur bony nucleus diameter exceeded 3 mm (group A) or retarded if either this nucleus was absent (subgroup B1) or its diameter was <3 mm (subgroup B2). DQ was evaluated with the Brunet-Lezine test. RESULTS: In 44.3% of cases BM was either delayed (23.5%) or severely delayed (20.8%). The risk of BM retardation was higher in the patients with athyreosis than in the remaining patients (41/57 vs 44/135, chi(2)=25.13, P<0.005). BM-retarded infants showed a more severe biochemical picture of CH at birth and a lower DQ at the age of one Year compared with the group A patients. If compared with infants of subgroup B2 those of subgroup B1 exhibited significantly lower T(4) levels at birth and a more frequent association with athyreosis (70.0 vs 30.0%; chi(2)=7.49, P<0.01), whereas DQ was superimposable in both subgroups. CONCLUSIONS: (a) BM at birth is delayed in almost half of CH patients and (b) CH severity per se can affect DQ at the age of 1 Year irrespective of other variables related to therapy.

Recovery of a telomere-truncated chromosome via a compensating translocation in maize

Genome ◽  
2011 ◽  
Vol 54 (3) ◽  
pp. 184-195 ◽  
Author(s):  
Robert T. Gaeta ◽  
Tatiana V. Danilova ◽  
Changzeng Zhao ◽  
Rick E. Masonbrink ◽  
Morgan E. McCaw ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Fluorescent In Situ Hybridization ◽  
Transgene Expression ◽  
De Novo ◽  
Extra Chromosome ◽  
Single Gene ◽  
B Chromosomes ◽  
Chromosome 1 ◽  
Chromosome 6

Maize-engineered minichromosomes are easily recovered from telomere-truncated B chromosomes but are rarely recovered from A chromosomes. B chromosomes lack known genes, and their truncation products are tolerated and transmitted during meiosis. In contrast, deficiency gametes resulting from truncated A chromosomes prevent their transmission. We report here a de novo compensating translocation that permitted recovery of a large truncation of chromosome 1 in maize. The truncation (trunc-1) and translocation with chromosome 6 (super-6) occurred during telomere-mediated truncation experiments and were characterized using single-gene fluorescent in situ hybridization (FISH) probes. The truncation contained a transgene signal near the end of the broken chromosome and transmitted together with the compensating translocation as a heterozygote to approximately 41%–55% of progeny. Transmission as an addition chromosome occurred in ~15% of progeny. Neither chromosome transmitted through pollen. Transgene expression (Bar) cosegregated with trunc-1 transcriptionally and phenotypically. Meiosis in T1 plants revealed eight bivalents and one tetravalent chain composed of chromosome 1, trunc-1, chromosome 6, and super-6 in diplotene and diakinesis. Our data suggest that de novo compensating translocations allow recovery of truncated A chromosomes by compensating deficiency in female gametes and by affecting chromosome pairing and segregation. The truncated chromosome can be maintained as an extra chromosome or together with the super-6 as a heterozygote.

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