Validating clinical characteristic of primary failure of eruption (PFE) associated with PTH1R variants

Abstract Background Primary failure of eruption (PFE) is a hereditary condition, and linkage with variants in the PTH1R gene has been demonstrated in many cases. The clinical severity and expression of PFE is variable, and the genotype–phenotype correlation remains elusive. Further, the similarity between some eruption disorders that are not associated with PTH1R alterations is striking. To better understand the genotype–phenotype correlation, we examined the relationship between the eruption phenotype and PTH1R genotype in 44 patients with suspected PFE and 27 unaffected relatives. Sanger sequencing was employed to analyze carefully selected PFE patients. Potential pathogenicity of variants was evaluated against multiple genetic databases for function prediction and frequency information. Results Mutational analysis of the PTH1R coding sequence revealed 14 different variants in 38 individuals (30 patients and 8 first-degree relatives), 9 exonic and 5 intronic. Their pathogenicity has been reported and compared with the number and severity of clinical signs. In 72.7% of patients with pathogenic variants, five clinical and radiographic criteria have been found: involvement of posterior teeth, involvement of the distal teeth to the most mesial affected, supracrestal presentation, altered vertical growth of the alveolar process and posterior open-bite. In cases with mixed dentition (3), the deciduous molars of the affected quadrant were infraoccluded. Discussion The probability of an affected patient having a PTH1R variant is greater when five specific clinical characteristics are present. The likelihood of an eruption defect in the absence of specific clinical characteristics is rarely associated with a PTH1R mutation. Conclusions We report here that systematic clinical and radiographic observation using a diagnostic rubric is highly valuable in confirming PFE and offers a reliable alternative for accurate diagnosis.

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Primary failure of eruption: Clinical and genetic findings in the mixed dentition

The Angle Orthodontist ◽

10.2319/062717-430.1 ◽

2018 ◽

Vol 88 (3) ◽

pp. 275-282 ◽

Cited By ~ 5

Author(s):

Cristina Grippaudo ◽

Concetta Cafiero ◽

Isabella D'Apolito ◽

Beatrice Ricci ◽

Sylvia A. Frazier-Bowers

Keyword(s):

Clinical Evidence ◽

Mutational Analysis ◽

Mixed Dentition ◽

Permanent Teeth ◽

Phenotype Correlation ◽

Posterior Teeth ◽

Coding Regions ◽

Primary Failure Of Eruption ◽

Parathyroid Hormone 1 Receptor ◽

In Silico Analyses

ABSTRACT Objective: To test the hypothesis that mutations in the parathyroid hormone 1 receptor (PTH1R) include effects in both primary and permanent teeth. Materials and Methods: DNA was extracted from saliva samples of 29 patients (8 familial and 21 sporadic) who presented with clinical evidence of infraoccluded teeth, and their unaffected relatives (N = 22). Sequencing followed by mutational analysis of the coding regions of PTH1R gene was completed for all individuals (N = 29). Results: Eight of 29 cases revealed a heterozygous pathogenic variant in the PTH1R gene; five of eight variants represented distinct mutations based on comparison with the dbSNP, HGMD, and ESP databases. One mutation (c.1765 T>C p.Trp89Arg) was found to segregate within a family (n = 3). In silico analyses for all variants revealed a putative pathogenic effect. A genotype-phenotype correlation was reported as defined by a functional mutation in PTH1R and corresponding effects on one or more posterior teeth only; unilateral or bilateral involvement, infraoccluded primary teeth. Conclusions: Novel mutations were reported in the PTH1R gene that included PFE-affected primary molars, thus providing the basis for using a genetic diagnostic tool for early diagnosis leading to proper management.

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Noninvasive and Multidisciplinary Approach to the Functional and Esthetic Rehabilitation of Amelogenesis Imperfecta: A Pediatric Case Report

Case Reports in Dentistry ◽

10.1155/2014/127175 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 5

Author(s):

Juliana Feltrin de Souza ◽

Camila Maria Bullio Fragelli ◽

Marco Aurélio Benini Paschoal ◽

Edson Alves Campos ◽

Leonardo Fernandes Cunha ◽

...

Keyword(s):

Case Report ◽

Composite Resin ◽

Preventive Treatment ◽

Open Bite ◽

Amelogenesis Imperfecta ◽

Mixed Dentition ◽

Anterior Open Bite ◽

Posterior Teeth ◽

Anterior Teeth

Case Report. An 8-year-old girl with amelogenesis imperfecta (AI) reported unsatisfactory aesthetics, difficulty in mastication, and dental hypersensitivity. The intraoral examination observed mixed dentition, malocclusion in anteroposterior relationships, anterior open bite, and dental asymmetry. A hypoplastic form of AI was diagnosed in the permanent dentition. A multidisciplinary planning was performed and divided into preventive, orthopedic, and rehabilitation stages. Initially, preventive treatment was implemented, with fluoride varnish applications, in order to protect the fragile enamel and reduce the dental sensitivity. In the second stage, the patient received an interceptive orthopedic treatment to improve cross-relationship of the arches during six months. Finally, the rehabilitation treatment was executed to establish the vertical dimension. In the posterior teeth, indirect composite resin crowns were performed with minimally invasive dental preparation. Direct composite resin restorations were used to improve the appearance of anterior teeth.Follow-Up. The follow-up was carried out after 3, 6, 12, and 18 months. After 18 months of follow-up, The restoration of integrity, oral hygiene, and patient satisfaction were observed .Conclusion. Successful reduction of the dental hypersensitivity and improvement of the aesthetic and functional aspects as well as quality of life were observed.

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Mutational Analysis and Genotype-Phenotype Correlation of 29 Unrelated Japanese Patients With X-linked Adrenoleukodystrophy

Archives of Neurology ◽

10.1001/archneur.56.3.295 ◽

1999 ◽

Vol 56 (3) ◽

pp. 295 ◽

Cited By ~ 38

Author(s):

Hiroki Takano ◽

Ryoko Koike ◽

Osamu Onodera ◽

Ryogen Sasaki ◽

Shoji Tsuji

Keyword(s):

Mutational Analysis ◽

Japanese Patients ◽

Phenotype Correlation ◽

Genotype Phenotype Correlation

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Genotype–phenotype Correlation in Children with Pheochromocytoma and Paraganglioma

World Journal of Endocrine Surgery ◽

10.5005/jp-journals-10002-1193 ◽

2016 ◽

Vol 8 (3) ◽

pp. 208-211

Author(s):

Nalini Shah ◽

Vijaya Sarathi ◽

M Sabaretnam

Keyword(s):

Genetic Testing ◽

Clinical Characteristics ◽

Cost Effective ◽

Germline Mutations ◽

Phenotype Correlation ◽

Biochemical Phenotype ◽

Genotype Phenotype Correlation ◽

Cluster 2

ABSTRACT Pheochromocytoma/paraganglioma (PPGL) have been reported to have germline mutations in more than 15 genes. PPGL diagnosed during childhood have the highest heritability (up to 80%). PPGL associated genes are classified into two clusters; cluster 1 (VHL, SDHx, EPAS1, PDH1, PDH2, FH, MDH2) and cluster 2 (RET, NF-1, TMEM127, MAX). Cluster 1 genes associated PPGL are norepinephrine secreting whereas cluster 2 genes associated PPGL are epinephrine secreting. In children with PPGL, VHL mutations are the most common followed by SDHB and SDHD. Bilateral PCC are frequent in patients with VHL mutations whereas extra-adrenal PGL are frequent in SDHx mutations. SDHB related PPGL are frequently malignant. Genetic testing should be performed in all children with PPGL and prioritization of genetic testing based on clinical characteristics (extra-paraganglial manifestations, location and number of PPGL, biochemical phenotype and metastasis) may be cost-effective. How to cite this article Sarathi V, Sabaretnam M, Shah N. Genotype–phenotype Correlation in Children with Pheochromocytoma and Paraganglioma. World J Endoc Surg 2016;8(3):208-211.

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A Genotype-Phenotype Correlation of Haemophilia a in Victorian Patients with a Description of Novel Mutations

Blood ◽

10.1182/blood-2018-99-112721 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2498-2498

Author(s):

Shreerang Sirdesai ◽

Kerryn Weekes ◽

Asif Alam ◽

Huyen A Tran ◽

Christopher Barnes ◽

...

Keyword(s):

In Silico ◽

Family Members ◽

In Silico Analysis ◽

Clinical Severity ◽

Missense Mutations ◽

Phenotype Correlation ◽

Novel Mutations ◽

Mild Phenotype ◽

Genotype Phenotype Correlation ◽

Silico Analysis

Abstract Aim: Hemophilia A (HA) is caused by abnormalities in the Factor VIII gene. Certain abnormalities correlate with disease severity. Here, we report the genotype-phenotype correlation for all Victorian HA patients. Methods: Using the Australian Bleeding Disorders Registry, Victorian HA patients were identified. All genetic testing was conducted at Southern Health. The testing algorithm is summarized in Figure 1. Mutations were compared with the list of known Factor 8 mutations on the Champ and EAHAD F8 Variant Databases. A PubMed search was undertaken for any mutations not on either database. If this too was unrevealing, the mutation was designated novel. In-silico analysis was conducted on all novel mutations using three open-access, online prediction tools: a) Mutation Taster; b) Poly-Phen 2; c) Human Splice Site Predictor. Results: 318 patients with matched clinical and genetic records were identified. 275 had known FVIII mutations and 36 novel FVIII mutations were discovered. Eight patients (3%) had no mutations identified. (Table 1) In severe HA the intron-22 inversion was the most common mutation (47/122, 38%). Missense mutations predominated in mild and moderate HA. Inhibitors were present in 44/318 patients, the majority of whom had 26/44 (59%) severe HA. 20/36 novel mutations (55%) were associated with severe HA, 12/36 (33%) with mild HA and 4/36 (11%) with a moderate HA. Novel mutations associated with non-severe phenotypes were mostly missense mutations (15/16); More diversity was seen in the novel mutations causing a severe HA with a fairly even distribution of mutations: missense (7/20), nonsense (4/20) and small deletions and insertions (8/20). One large deletion involving a 6.5kb region of exon 26, as well as one duplication of exons 7 to 9 - was seen in the severe group. In-silico analysis predicted that all novel severe HA mutations were likely to be pathogenic.Inhibitors were seen in 7 patients with novel mutations. Of the 36 novel mutations we described, 9/36 (25%) were seen in other family members - often female carriers. All 9 mutations caused a severe phenotype which is not unexpected given that the screening and testing of family members would be unlikely to take place in patients who have a mild phenotype and rarely require supportive medical care Conclusion: This study adds 36 novel mutations to the currently known FVIII haemophilic mutations. It also confirms that the frequency and correlative clinical severity of known genetic mutations in the Victorian HA cohort is similar to that described internationally. Disclosures No relevant conflicts of interest to declare.

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Genotype-Phenotype Correlation Study and Mutational Analysis in a Chinese Cohort with 21-Hydroxylase Deficiency

SSRN Electronic Journal ◽

10.2139/ssrn.3205563 ◽

2018 ◽

Author(s):

Wenyu Jia ◽

Zequn Li ◽

Xiangdeng Cheng ◽

Hui Ying ◽

Fang Zhong ◽

...

Keyword(s):

Mutational Analysis ◽

Correlation Study ◽

Phenotype Correlation ◽

Hydroxylase Deficiency ◽

Genotype Phenotype Correlation ◽

Chinese Cohort ◽

21 Hydroxylase Deficiency

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Molecular Basis of Recessive Dystrophic Epidermolysis Bullosa: Genotype/Phenotype Correlation in a Case of Moderate Clinical Severity

Journal of Investigative Dermatology ◽

10.1111/1523-1747.ep12329600 ◽

1996 ◽

Vol 106 (1) ◽

pp. 119-124 ◽

Cited By ~ 58

Author(s):

Hiroshi Shimizu ◽

John A. McGrath ◽

Angela M. Christiano ◽

Takeji Nishikawa ◽

Jouni Uitto

Keyword(s):

Epidermolysis Bullosa ◽

Molecular Basis ◽

Clinical Severity ◽

Phenotype Correlation ◽

Dystrophic Epidermolysis Bullosa ◽

Genotype Phenotype Correlation ◽

Recessive Dystrophic Epidermolysis Bullosa

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Mutational analysis and genotype/phenotype correlation in Turkish Charcot-Marie-Tooth Type 1 and HNPP patients

Clinical Genetics ◽

10.1034/j.1399-0004.2000.580511.x ◽

2000 ◽

Vol 58 (5) ◽

pp. 396-402 ◽

Cited By ~ 23

Author(s):

N Bissar-Tadmouri ◽

Y Parman ◽

L Boutrand ◽

F Deymeer ◽

P Serdaroglu ◽

...

Keyword(s):

Mutational Analysis ◽

Phenotype Correlation ◽

Charcot Marie Tooth ◽

Genotype Phenotype Correlation ◽

Tooth Type

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Detailed clinical features and genotype–phenotype correlation in an OTOF-related hearing loss cohort in Japan

Human Genetics ◽

10.1007/s00439-021-02351-7 ◽

2021 ◽

Author(s):

Yoh-ichiro Iwasa ◽

Shin-ya Nishio ◽

Hidekane Yoishimura ◽

Akiko Sugaya ◽

Yuko Kataoka ◽

...

Keyword(s):

Hearing Loss ◽

Cochlear Implantation ◽

Clinical Characteristics ◽

Clinical Information ◽

Auditory Neuropathy ◽

Hearing Level ◽

Phenotype Correlation ◽

Profound Hearing Loss ◽

Genotype Phenotype Correlation ◽

Auditory Performance

AbstractMutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype–phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype–phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.6%) showed a “typical” phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85–90% of the patients showed a hearing level of 20–39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed “true” auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype–phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype–phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.

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