scholarly journals High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype–Phenotype Correlation

2015 ◽  
Vol 36 (11) ◽  
pp. 1052-1063 ◽  
Author(s):  
Kitiwan Rojnueangnit ◽  
Jing Xie ◽  
Alicia Gomes ◽  
Angela Sharp ◽  
Tom Callens ◽  
...  
Keyword(s):  
Short Stature ◽  
Noonan Syndrome ◽  
Missense Mutations ◽  
Phenotype Correlation ◽  
Pulmonic Stenosis ◽  
Genotype Phenotype Correlation ◽  
High Incidence

scholarly journals PTPN11 Mutations Are Associated with Mild Growth Hormone Resistance in Individuals with Noonan Syndrome

2005 ◽  
Vol 90 (9) ◽  
pp. 5377-5381 ◽  
Author(s):  
G. Binder ◽  
K. Neuer ◽  
M. B. Ranke ◽  
N. E. Wittekindt
Keyword(s):  
Short Stature ◽  
Noonan Syndrome ◽  
Tyrosine Phosphatase ◽  
Pcr Amplification ◽  
Heterozygous Mutation ◽  
Missense Mutations ◽  
Pulmonic Stenosis ◽  
Gh Secretion ◽  
Igf I ◽  
Igfbp 3

Abstract Context: Noonan syndrome is frequently associated with an unclear disturbance of GH secretion. Half the individuals with Noonan syndrome carry a heterozygous mutation of the nonreceptor-type protein tyrosine phosphatase, Src homology region 2-domain phosphatase-2 (SHP-2), encoded by PTPN11, which has a role in GH receptor signaling. Objective: The objective of this study was to compare GH secretion and IGF-I/IGF-binding protein-3 (IGFBP-3) levels of the SHP-2 mutation-positive (mut+ group) vs. mutation-negative individuals (mut− group). Design, Setting, and Patients: All children presenting to us with short stature plus at least three typical anomalies of Noonan syndrome or pulmonic stenosis during the last 5 yr (n = 29; 10 females and 19 males) were recruited. Auxological data, dysmorphic features, and cardiac morphology were documented. Hormone levels were measured by RIA. All coding exons of PTPN11 were sequenced after PCR amplification. Intervention: A prepubertal subgroup (n = 11) was treated with recombinant human GH (rhGH) to promote growth. Results: Sequencing yielded 11 different PTPN11 missense mutations in 16 of the 29 patients (55% mut+). Pulmonic stenosis (81 vs. 15%; P = 0.0007) and septal defects (63 vs. 15%; P = 0.02) were more frequently found in the mut+ group, whereas minor anomalies, cryptorchidism, and learning disabilities were as frequent in the mut+ group as in the mut− group. The mut+ group was younger at presentation (mean ± sd, 5.1 ± 2.7 vs. 10.3 ± 5.2 yr; P = 0.002), but not significantly shorter [−3.15 ± 0.92 vs. −3.01 ± 1.35 height sd score (SDS)]. IGF-I levels (−2.03 ± 0.69 vs. −1.13 ± 0.89 SDS; P = 0.005) and IGFBP-3 levels (−0.92 ± 1.26 vs. 0.40 ± 1.08 SDS; P = 0.006) were significantly lower in the mut+ group. In contrast, GH levels showed a tendency to be higher in the mut+ group during spontaneous secretion at night and arginine stimulation (P ≥ 0.075, not significant). The mean change in height SDS after 1 yr of rhGH therapy (0.043 mg/kg·d) was +0.66 ± 0.21 in the mut+ group (n = 8), but +1.26 ± 0.36 in the mut− group (n = 3; P = 0.007). Conclusions: Our data suggest that SHP-2 mutations in Noonan syndrome cause mild GH resistance by a postreceptor signaling defect, which seems to be partially compensated for by elevated GH secretion. This defect may contribute to the short stature phenotype in children with SHP-2 mutations and their relatively poor response to rhGH.

scholarly journals PTPN11 Mutations in Noonan Syndrome: Molecular Spectrum, Genotype-Phenotype Correlation, and Phenotypic Heterogeneity

2002 ◽  
Vol 70 (6) ◽  
pp. 1555-1563 ◽  
Author(s):  
Marco Tartaglia ◽  
Kamini Kalidas ◽  
Adam Shaw ◽  
Xiaoling Song ◽  
Dan L. Musat ◽  
...  
Keyword(s):  
Noonan Syndrome ◽  
Phenotypic Heterogeneity ◽  
Molecular Spectrum ◽  
Phenotype Correlation ◽  
Genotype Phenotype Correlation

Ulerythema Ophryogenes, A Rarely Reported Cutaneous Manifestation of Noonan Syndrome: Case Report and Review of the Literature

2013 ◽  
Vol 17 (3) ◽  
pp. 212-218 ◽  
Author(s):  
Kayi Li ◽  
Mary Ann Thomas ◽  
Richard M. Haber
Keyword(s):  
Case Report ◽  
Noonan Syndrome ◽  
Cutaneous Manifestation ◽  
Review Of The Literature ◽  
Phenotype Correlation ◽  
Genetic Condition ◽  
Genotype Phenotype Correlation

Background: Ulerythema ophryogenes (also known as keratosis pilaris atrophicans faciei) is a rarely reported cutaneous manifestation of Noonan syndrome. Objective: Recognizing ulerythema ophryogenes as a cutaneous association in Noonan syndrome may aid in the diagnosis of this relatively common genetic condition. Methods: We present a case of a patient with Noonan syndrome and ulerythema ophryogenes associated with a SOS1 mutation and review the literature on this association. Results: To the best of our knowledge, this is the second case of Noonan syndrome proven to be due to an SOS1 mutation in which ulerythema ophryogenes was clinically recognized and specifically diagnosed. Conclusions: The presence of ulerythema ophryogenes in a patient with Noonan syndrome increases the likelihood of a SOS1 mutation. Further reports by dermatologists and medical geneticists documenting ulerythema ophryogenes and not just descriptions of sparse or absent eyebrows will help support this genotype-phenotype correlation.

scholarly journals Mutation analysis of the ATP7B gene and genotype-phenotype correlation in Chinese patients with Wilson disease

2021 ◽  
Author(s):  
Mingming Li ◽  
Jing Ma ◽  
Wenlong Wang ◽  
Xu Yang ◽  
Kaizhong Luo
Keyword(s):  
Wilson Disease ◽  
Large Scale ◽  
Allelic Frequency ◽  
Chinese Patients ◽  
Missense Mutations ◽  
Onset Age ◽  
Phenotype Correlation ◽  
Novel Mutations ◽  
Nonsense Mutations ◽  
Genotype Phenotype Correlation

Abstract AIM To discover the novel ATP7B mutations in 103 southern Chinese patients with Wilson disease (WD), and to determine the spectrum and frequency of mutations in the ATP7B gene and genotype-phenotype correlation in a large-scale sample of Chinese WD patients. Methods One hundred three WD patients from 101 unrelated families in southern China were enrolled in this study. Genomic DNA was extracted from the peripheral blood. Direct sequencing of all 21 exons within ATP7B was performed. Subsequently, an extensive study of the overall spectrum and frequency of ATP7B mutations and genotype-phenotype correlation was performed in all Chinese patients eligible from the literature, combined with the current southern group.Results In 103 patients with WD, we identified 48 different mutations (42 missense mutations, 4 nonsense mutations and 2 frameshifts). Of these, 7 mutations had not been previously reported: 1510_1511insA, 2075T>C (Leu692Pro), 2233C>A (Leu745Met), 3209C>G (Pro1070Arg),3677C>T (Thr1226Ile), 3793G>T (Val1265Leu) and 3824T>C (Leu1275Ser). The 2333G>T (Arg778 Leu) at exon 8, was the most common mutation with an allelic frequency of 18.8%, followed by 2975C>T (Pro992Leu) at exon 13, with an allelic frequency of 13.4%. In the comprehensive study, 233 distinct mutations were identified, including 154 missense mutations, 23 nonsense mutations and 56 frameshifts. Eighty-five variants were identified as novel mutations. The 2333G>T (Arg778 Leu) and 2975C>T (Pro992Leu) were the most common mutations, with allelic frequencies of 28.6% and 13.0%, respectively. Exons 8, 12, 13, 16 and 18 were recognised as hot spot exons. Phenotype-genotype correlation analysis suggested that 2333G>T (Arg778 Leu) was significantly associated with lower levels of serum ceruloplasmin (P=0.034). 2975C>T (Pro992Leu) was correlated with earlier age of disease onset (P=0.002). Additionally, we found that the 3809A>G (Asn1270Ser) mutation significantly indicated younger onset age (P=0.012), and the 3884C>T (Ala1295Val) mutation at exon 18 was significantly associated with hepatic presentation (P=0.048). Moreover, the patients with mixed presentation displayed the initial WD features at an older onset age than the groups with either liver disease or neurological presentation (P=0.039, P=0.015, respectively). No significant difference was observed in the presence of KF rings among the three groups with different clinical manifestations. Conclusion In this study, we identified seven novel mutations in 103 WD patients from the southern part of China, which could enrich the previously established mutational spectrum of the ATP7B gene. Moreover, we tapped into a large-scale study of a Chinese WD cohort to characterise the overall phenotypic and genotypic spectra and assess the association between genotype and phenotype, which enhances the current knowledge about the population genetics of WD in China.

scholarly journals A Novel Missense Variant of HOXD13 Caused Atypical Synpolydactyly by Impairing the Downstream Gene Expression and Literature Review for Genotype–Phenotype Correlations

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruiji Guo ◽  
Xia Fang ◽  
Hailei Mao ◽  
Bin Sun ◽  
Jiateng Zhou ◽  
...  
Keyword(s):  
Limb Development ◽  
Missense Variant ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Phenotype Correlation ◽  
Mutation Site ◽  
Genotype Phenotype Correlation ◽  
Α Helix ◽  
Severe Degree ◽  
Hands And Feet

Synpolydactyly (SPD) is a hereditary congenital limb malformation with distinct syndactyly designated as SPD1, SPD2, and SPD3. SPD1 is caused by mutations of HOXD13, which is a homeobox transcription factor crucial for limb development. More than 143 SPD patients have been reported to carry HOXD13 mutations, but there is a lack of genotype–phenotype correlation. We report a novel missense mutation of c. 925A > T (p.I309F) in an individual with atypical synpolydactyly inherited from her father with mild clinodactyly and three other different alanine insertion mutations in HOXD13 identified by whole exome sequencing (WES) in 12 Chinese SPD families. Unlike polyalanine extension, which tends to form α-helix and causes protein aggregation in the cytoplasm as shown by molecular simulation and immunofluorescence, the c. 925A > T mutation impairs downstream transcription of EPHA7. We compiled literature findings and analyzed genotype–phenotype features in 173 SPD individuals of 53 families, including 12 newly identified families. Among the HOXD13-related individuals, mutations were distributed in three regions: polyalanine, homeobox, and non-homeobox. Polyalanine extension was the most common variant (45%), followed by missense mutations (32%) mostly in the homeobox compared with the loss-of-function (LOF) variants more likely in non-homeobox. Furthermore, a more severe degree and classic SPD were associated with polyalanine mutations although missense variants were associated with brachydactyly and syndactyly in hands and feet and LOF variants with clinodactyly in hands. Our study broadens the HOXD13 mutation spectrum and reveals the profile of three different variants and their severity of SPD, the genotype–phenotype correlation related to the HOXD13 mutation site provides clinical insight, including for genetic counseling.

Pathogenic/likely pathogenic variants in the SHOX, GHR and IGFALS genes among Indian children with idiopathic short stature

2020 ◽  
Vol 33 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Anil Kumar ◽  
Vandana Jain ◽  
Madhumita Roy Chowdhury ◽  
Manoj Kumar ◽  
Punit Kaur ◽  
...  
Keyword(s):  
Growth Factor ◽  
Short Stature ◽  
Serum Insulin ◽  
Significant Proportion ◽  
Idiopathic Short Stature ◽  
Insulin Like Growth Factor ◽  
Phenotype Correlation ◽  
Indian Children ◽  
Pathogenic Variants ◽  
Genotype Phenotype Correlation

AbstractBackgroundOur objective was to estimate the prevalence of pathogenic/likely pathogenic variants in the SHOX, GHR, and IGFALS genes among Indian children with idiopathic short stature (ISS), and assess the genotype-phenotype correlation.MethodsWe recruited 61 children with short stature, who were born appropriate for gestational age, had no obvious dysmorphism or disproportion, and in whom step-wise investigative work-up (including provocative growth hormone test) was normal. Multiplex ligation-dependent probe amplification was undertaken for identifying deletions/duplications in the SHOX gene. Bidirectional sequencing was performed for identifying variants in the SHOX and GHR genes in all, and for the IGFALS gene in those with serum insulin-like growth factor-1 (IGF-1) <−1 standard deviation. The genotype-phenotype correlation was studied.ResultsFour children (6.5%) had pathogenic heterozygous variants in the SHOX gene, with one child each having duplication of exon 5, splice site point variant c.278-1G > C in exon 3, partial deletion and complete deletion. None of the patients had pathogenic variants in the GHR gene. Of the 39 patients in whom the IGFALS gene was sequenced, novel heterozygous likely pathogenic variants were found in two children. One had the frameshift variant c.764_765insT, p.A265Gfs*114. The second had the missense variant c.1793G > A, p.R598H predicted by MutationTaster as ‘disease causing’, and indicated by the protein-modelling study as having compromised binding with IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) due to altered conformation of the interacting loop.ConclusionsPathogenic variants in the SHOX and IGFALS genes account for a significant proportion of Indian children with ISS. Further molecular studies using next generation sequencing are needed to gain insight into pathophysiological mechanisms and effective treatment strategies for ISS.

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

Blood ◽  
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.

scholarly journals Case Report: Amyloidosis Cutis Dyschromica: Dermoscopy and Reflectance Confocal Microscopy and Gene Mutation Analysis of a Chinese Pedigree

2021 ◽  
Vol 8 ◽  
Author(s):  
Hui Wang ◽  
Zhenyu Zhong ◽  
Xiuli Wang ◽  
Liyun Zheng ◽  
Yifan Wang ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Reflectance Confocal Microscopy ◽  
Pathological Examination ◽  
Missense Mutations ◽  
Phenotype Correlation ◽  
Rare Type ◽  
Genotype Phenotype Correlation ◽  
Imaging Characteristics

Background: Amyloidosis cutis dyschromica (ACD) is a rare type of primary localized cutaneous amyloidosis. Non-invasive techniques can provide important clues for early diagnosis.Objectives: To highlight the characteristic imaging changes of ACD under dermoscopy and reflectance confocal microscopy (RCM), investigate gene mutations in a Chinese Han pedigree of ACD, and analyze the genotype–phenotype correlation.Methods: Dermoscopy and RCM examinations were completed together for the pedigree, and the imaging characteristics were described. The diagnosis of ACD was confirmed by pathological examination. Sequencing was performed followed by bioinformatics and genotype–phenotype correlation. ACD-related articles published on PubMed between January 1970 and March 2021 were reviewed and summarized.Results: In ACD, dermoscopy showed patchy white hypopigmentation and brownish spots, stripes, or hyperpigmented blotches and patches. RCM showed a highly refractive substance with clumpy, dotted, and linear structures inside the papillary dermis. Sequencing identified glycoprotein non-metastatic melanoma protein B (GPNMB) missense mutations [c.393T&gt;G (p.Y131X; NM_001005340.2)] and a frameshift deletion mutation [c.719_720delTG (p.V240fs; NM_001005340.2)]. The ANNOtate VARiation (ANNOVAR) software predicted that c.393T&gt;G is a pathogenic mutation. The literature review found 14 mutations, namely, 5 (35.7%) frameshift mutations, 4 (28.6%) non-sense mutations, 4 (28.6%) missense mutations, and 1 (7.1%) splice site mutation. Blisters and epidermolysis were observed in several cases, but there was no significant association between clinical manifestations and mutations in ACD.Conclusions: This study was the first to combine dermoscopy and RCM to describe ACD. Two GPNMB gene mutations were reported in a Chinese ACD pedigree. The genotype–phenotype correlation was analyzed for the first time; however, there was no significant correlation.

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