PRPH2-Associated Macular Dystrophy in 4 Family Members with a Novel Mutation

Meesmann epithelial corneal dystrophy (MECD) is a rare dominantly inherited disorder that is characterized by corneal epithelial microcysts and is associated with mutations in the keratin 3 (KRT3) and keratin 12 (KRT12) genes. In this study, we report a novel mutation in the KRT12 gene in a Vietnamese pedigree with MECD. Slit-lamp examination was performed on each of the 7 recruited members of a Vietnamese family to identify characteristic features of MECD. After informed consent was obtained from each individual, genomic DNA was isolated from saliva samples and screening of KRT3and KRT12 genes was performed by Sanger sequencing. The proband, a 31-year-old man, complained of a 1-year history of eye irritation and photophobia. Slit-lamp examination revealed intraepithelial microcysts involving only the corneal periphery in each eye with clear central corneas and no stromal or endothelial involvement. Three family members demonstrated similar intraepithelial microcysts, but with diffuse involvement, extended from limbus to limbus. Sanger sequencing of KRT3 (exon 7) and KRT12 (exons 1 and 6) in the proband revealed a novel heterozygous KRT12 variant (c.1273G>A [p.Glu425Lys]) that was present in the three affected family members but was absent in the three family members with clear corneas. This study is the first report of a Vietnamese family affected with MECD, associated with an atypical peripheral corneal epithelial phenotype in the proband and a novel mutation in KRT12.

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A novel mutation in the conserved sequence of vascular endothelial growth factor receptor 3 leads to primary lymphoedema

Journal of International Medical Research ◽

10.1177/0300060518773264 ◽

2018 ◽

Vol 46 (8) ◽

pp. 3162-3171 ◽

Cited By ~ 3

Author(s):

Ting Dai ◽

Bohan Li ◽

Bo He ◽

Liwei Yan ◽

Liqiang Gu ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Novel Mutation ◽

Family Members ◽

Growth Factor Receptor ◽

Chinese Family ◽

Vascular Endothelial ◽

Healthy Controls ◽

Endothelial Growth Factor ◽

Congenital Lymphoedema

Objective To investigate whether lymphoedema in a Chinese family showed the hereditary and clinical characteristics of Milroy disease, an autosomal dominant form of congenital lymphoedema, typically characterized by chronic lower limb tissue swelling due to abnormal lymphatic vasculature development, and to perform mutational analyses of vascular endothelial growth factor receptor ( VEGFR)3. Methods Individuals from a three-generation family affected by congenital lymphoedema were clinically assessed for Milroy disease. Mutation analysis of VEGFR3 was performed using DNA from family members and healthy controls. Results Out of 20 family members, eight were diagnosed with hereditary lymphoedema. Mutation analyses revealed a novel mutation site for c.3163 G>A, resulting in a p.1055D>N mutation in the second tyrosine kinase domain of VEGFR3, which was present in affected individuals only (absent in all unaffected family members and 130 healthy controls). Computed functional analyses showed the mutation may lead to structural alterations with a probability of 0.99999 of being disease causing. Conclusion A novel mutation associated with Milroy disease was identified in a Chinese family, expanding our knowledge of VEGFR3 gene function and providing a potential molecular target for treating hereditary lymphoedema.

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Multiple Family Members With Delayed Cord Separtion and Combined Immunodeficiency With Novel Mutation in IKBKB

Frontiers in Pediatrics ◽

10.3389/fped.2020.00009 ◽

2020 ◽

Vol 8 ◽

Author(s):

Zobaida Alsum ◽

Mofareh S. AlZahrani ◽

Hamoud Al-Mousa ◽

Nouf Alkhamis ◽

Abdulkareem A. Alsalemi ◽

...

Keyword(s):

Novel Mutation ◽

Family Members ◽

Combined Immunodeficiency

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SAT-434 Phenotype and Genotype Analysis of Patients with Resistance to Thyroid Hormone β: A Single-Center Experience

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.873 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Karn Wejaphikul ◽

Prapai Dejkhamron ◽

Stefan Groeneweg ◽

W Edward Visser ◽

Kevalee Unachak ◽

...

Keyword(s):

Thyroid Hormone ◽

Mutation Analysis ◽

Novel Mutation ◽

Family Members ◽

Antithyroid Drugs ◽

Thyroid Function Tests ◽

Resistance To Thyroid Hormone ◽

The Mean ◽

The Impact

Abstract Introduction Resistance to thyroid hormone β (RTHβ) is caused by mutations in THRB, the gene that encodes thyroid hormone receptor β. The clinical phenotype is variable and may include goiter, tachycardia, and learning disability with or without hyperactive behavior. The biochemical hallmark of RTHβ is elevated T4 and T3 with non-suppressed TSH concentrations. We here describe the phenotype and genotype of three Thai patients diagnosed with RTHβ in a pediatric referral center. Patients had previously been misdiagnosed and inappropriately treated with antithyroid drugs (ATDs). Methods Clinical features and thyroid function tests (TFTs) of three unrelated RTHβ patients were retrospectively reviewed. Genomic DNA of the RTHβ patients and affected family members was amplified for exon 7-10 of the THRB gene and sequenced to identify mutation by Sanger sequencing. The impact of the p.L341V novel mutation on the affinity for T3 and T3-induced transcriptional activity was previously determined in vitro. Results Three female patients were diagnosed with RTHβ. All of them had been misdiagnosed with hyperthyroidism and treated with ATDs prior to referral. The mean age at diagnosis was 8 years. The main presenting symptoms were diffuse goiter and tachycardia. The mean duration of ATD treatment was 3 years. During the treatment, patients had fluctuating thyroid hormone and increased TSH levels. An older sister and mother of one patient also had similar TFTs abnormalities, for which the mother had undergone a subtotal thyroidectomy. RTHβ was diagnosed based on the high FT3 and FT4 with normal (non-suppressed) TSH concentrations and confirmed by mutation analysis. Anti-thyroid peroxidase, anti-thyroglobulin, and TSH receptor antibody (TRAb) were negative, excluding autoimmune thyroid disease. Heterozygous missense mutations of the THRB gene were identified in all patients and affected family members. Two mutations had been previously reported (p.R243W and p.L456F), and one mutation was novel (p.L341V). In vitro studies confirmed an important role of Leu341 in T3 binding of the TRβ and functional impairment of the p.L341V novel mutation and were reported separately. According to available literature, only nine Thai RTHβ patients (in three families) carrying three different mutations (p.G251V, p.M313T, and p.A317T) had been previously reported. Goiter was the most common clinical finding, and almost all patients had a history of receiving unnecessary treatment with ATDs. Conclusion We report a series of RTHβ patients carrying THRB gene mutations, including one novel mutation (p.L341V). Clinicians should be alert that RTHβ can be found in patients with goiter and tachycardia. Elevated T4 and T3 with non-suppressed TSH concentration is the main diagnostic clue for this disease. Mutation analysis allows definitive diagnosis of RTHβ and may help to avoid potential misdiagnosis and improper treatment.

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A hereditaer nonpolyposus colorectalis carcinoma szindrómás betegek szűrésének és szoros utánkövetésének fontossága egy családfa bemutatása kapcsán

Orvosi Hetilap ◽

10.1556/650.2017.30803 ◽

2017 ◽

Vol 158 (30) ◽

pp. 1182-1187

Author(s):

Gergely Kóder ◽

Judit Olasz ◽

László Tóth ◽

Hilda Urbancsek ◽

Csilla András ◽

...

Keyword(s):

Autosomal Dominant ◽

Novel Mutation ◽

Family Members ◽

Her Family ◽

Mmr Genes ◽

Gene Mutation Carrier ◽

Hereditary Nonpolyposis ◽

Dominant Disease ◽

Associated Tumors

Abstract: Introduction: Hereditary nonpolyposis colorectal carcinoma (HNPCC) is an autosomal dominant disease, which shows familial clustering. Aim: We would like to emphasize the importance of monitoring the HNPCC syndrome patients by presenting a case of a proven MMR gene mutation carrier and her family tree encompassing 10 years. Materials and method: To screen a suspected HNPCC Hungarian family member we are taking thorough family histories. If the diagnosis of HNPCC was further supported by immunohistology and the microsatellite status, sequencing of the MMR genes was carried out. Results: A novel mutation in exon 6 of the hMSH2 gene leading to the deletion of two nucleotide pairs [c.969-970delTC] was detected in our patient. During the 10-year follow-up period of our patient new HNPCC-associated tumors have developed in several family members. Conslusion: Close surveillance of the patient and its family members at risk was effective, although it requires compliance from the subjects. Orv Hetil. 2017; 158(30): 1182–1187.

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Clinical and Genetic Findings of Autosomal Recessive Bestrophinopathy (ARB)

Genes ◽

10.3390/genes10120953 ◽

2019 ◽

Vol 10 (12) ◽

pp. 953 ◽

Cited By ~ 3

Author(s):

Imen Habibi ◽

Yosra Falfoul ◽

Margarita G. Todorova ◽

Stefan Wyrsch ◽

Veronika Vaclavik ◽

...

Keyword(s):

Molecular Analysis ◽

Autosomal Recessive ◽

Novel Mutation ◽

Macular Dystrophy ◽

Phenotype Correlation ◽

Corrected Visual Acuity ◽

Light Rise ◽

Autosomal Recessive Bestrophinopathy ◽

Biallelic Mutations

Mutations in BEST1 cause several phenotypes including autosomal dominant (AD) Best vitelliform macular dystrophy type 2 (BVMD), AD vitreo-retino-choroidopathy (ADVIRC), and retinitis pigmentosa-50 (RP50). A rare subtype of Bestrophinopathy exists with biallelic mutations in BEST1. Its frequency is estimated to be 1/1,000,000 individuals. Here we report 6 families and searched for a genotype-phenotype correlation. All patients were referred due to reduced best-corrected visual acuity (BCVA), ranging from 0.1/10 to 3/10. They all showed vitelliform lesions located at the macula, sometimes extending into the midperiphery, along the vessels and the optic disc. Onset of the disease varied from the age of 3 to 25 years. Electrooculogram (EOG) revealed reduction in the EOG light rise in all patients. Molecular analysis revealed previously reported mutations p.(E35K);(E35K), p.(L31M);(L31M), p.(R141H);(A195V), p.(R202W);(R202W), and p.(Q220*);(Q220*) in five families. One family showed a novel mutation: p.(E167G);(E167G). All mutations were heterozygous in the parents. In one family, heterozygous children showed various reductions in the EOG light rise and autofluorescent deposits. Autosomal recessive Bestrophinopathy (ARB), although rare, can be recognized by its phenotype and should be validated by molecular analysis. Genotype-phenotype correlations are difficult to establish and will require the analysis of additional cases.

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A NEW MACULAR DYSTROPHY SECONDARY TO A NOVEL MUTATION IN THE PROMININ 1 (PROM1) GENE

Retinal Cases & Brief Reports ◽

10.1097/icb.0000000000000405 ◽

2017 ◽

Vol 11 ◽

pp. S62-S64

Author(s):

Sandeep Randhawa ◽

Mithlesh Sharma

Keyword(s):

Novel Mutation ◽

Macular Dystrophy

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Molecular Diagnosis of One Pedigree with Protein S Deficiency and Antithrombin Deficiency

Blood ◽

10.1182/blood.v120.21.5140.5140 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5140-5140

Author(s):

Rong-Fu Zhou ◽

Hong Tao ◽

Jian Ouyang ◽

Xian Zhang ◽

Yonggong Yang ◽

...

Keyword(s):

Conflicts Of Interest ◽

Novel Mutation ◽

Color Doppler ◽

Femoral Vein ◽

Family Members ◽

Protein S ◽

Heterozygous Mutation ◽

Sequencing Analysis ◽

Antithrombin Deficiency ◽

Exon 4

Abstract Abstract 5140 Objective To identify gene mutations for one patient and his family members with protein S and antithrombin deficiency. Methods ELISA were used to detect protein S (PS), protein C (PC) and antithrombin (AT) activities for the proband and family members, respectively. The genomic DNA was extracted from the peripheral blood of proband and family members. All exons and their flanks of protein S gene and antithrombin gene were amplified by polymerase chain reaction (PCR). The PCR products were sequenced directly. The mutation-related exons of his famliy members were amplified by PCR and sequenced directly. Results The proband was a 49-year-old male. He presented with sudden left lower extremity swelling and pain without casues. Regular examination revealed that his APTT, PT, and TT were all in normal levels, but D- dimmer was 5. 62mg/L, Color doppler ultrasonography showed thrombosis in his left femoral vein. The activity of PS for his family members was ‡1 0%, ‡2 0%, ‡3 0%, ‡4 130. 8%, ‡5 8. 4%, ‡1 0%, ‡2 0%, and that of AT was ‡1 129. 1%, ‡2 51. 9%, ‡3 73.2%, ‡4 119. 1%, ‡5 136. 2%, ‡1 65. 5% and ‡2 60. 1%, respectively. The sequencing analysis showed that a heterozygous missense mutation G68395T (NG_009813. 1) was detected in Exon 4 of PS gene leading to the substitution of Arg90 by Leu (NP_000304. 2) for the propositus. The heterozygous mutation (Arg90Leu) was also found in other family members. A heterozygous (nonsense) mutation G12444A (NG_012462. 1) was detected in Exon 4 of AT gene leading to Trp257Ter (NP_000479. 1) for the propositus. The mutation (Trp257Ter) was found in other family members with reduced activity of AT. These two mutations (G68395T in PS gene and G12444A in AT gene) were not reported before and were thus novel ones. Conclusion The novel mutation G68395T in PS gene and G12444A in AT gene might be the causes of deficiency of PS and AT for the family. Disclosures: No relevant conflicts of interest to declare.

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Novel MFSD8 Variants in a Chinese Family with Nonsyndromic Macular Dystrophy

Journal of Ophthalmology ◽

10.1155/2021/6684045 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Qin Xiang ◽

Yanna Cao ◽

Hongbo Xu ◽

Zhijian Yang ◽

Liang Tang ◽

...

Keyword(s):

Family Members ◽

Major Facilitator Superfamily ◽

Chinese Family ◽

Macular Dystrophy ◽

Compound Heterozygous ◽

The Novel ◽

Pathogenic Variants ◽

Compound Heterozygous Variants ◽

Major Facilitator ◽

Mfsd8 Gene

Purpose. To identify the molecular etiology of a Chinese family with nonsyndromic macular dystrophy. Methods. Ophthalmic examinations were performed, and genomic DNA was extracted from available family members. Whole exome sequencing of two members (the proband and her unaffected mother) and Sanger sequencing in available family members were performed to screen potential pathogenic variants. Results. Novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the major facilitator superfamily domain containing 8 gene (MFSD8) were suspected to be involved in this family’s macular dystrophy phenotype. The novel c.1066C>T variant in the MFSD8 gene probably resulted in substitution of serine for proline at the 356th residue and was predicted to be “uncertain significance” through in silico analyses. The novel c.1102+2T>C variant in the MFSD8 gene was likely to affect the splicing form and predicted to be “pathogenic.” Conclusion. The novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the MFSD8 gene are likely responsible for the isolated macular dystrophy phenotype in this family. This study enlarged the MFSD8 gene mutant spectrum and might provide more accurate genetic counseling for this family.

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Case report on novel mutation in SPAST gene in Polish family with spastic paraplegia

BMC Neurology ◽

10.1186/s12883-019-1561-6 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Aleksandra Klimkowicz-Mrowiec ◽

Anna Dziubek ◽

Malgorzata Sado ◽

Marek Karpiński ◽

Agnieszka Gorzkowska

Keyword(s):

Case Report ◽

Genetic Testing ◽

Family History ◽

Lower Limb ◽

Hereditary Spastic Paraplegia ◽

Novel Mutation ◽

Family Members ◽

Spastic Paraplegia ◽

Limb Spasticity ◽

Lower Limb Spasticity

Abstract Background Hereditary spastic paraplegia is a large group of degenerative, neurological disorders characterized by progressive lower limb spasticity and weakness. The disease was investigated precisely but still clinicians often make incorrect or late diagnosis. Our aim was to investigate the genetic background and clinical phenotype of spastic paraplegia in large Polish family. Case presentation A 37 years old woman presented with 4-year history of walking difficulties. On neurological examination, she had signs of upper motor lesion in lower extremities. She denied sphincter dysfunction and her cognition was normal. Her family history was positive for individuals with gait problems. The initial diagnosis was familial spastic paraplegia. Genetic testing identified a novel mutation in SPAST gene. All available family members were examined and had genetic testing. The same mutation in SPAST gene was identified in other affected family members. All patients caring the mutation presented with different phenotypes. Conclusion This study presents a family with spastic paraplegia due to a novel mutation c.1390G›T(p.Glu464Term) in SPAST gene. Affected individuals showed a range of phenotypes that varied in their severity. This case report demonstrates, the signs of hereditary spastic paraplegia can be often misdiagnosed with other diseases. Therefore genetic testing should always be considered in patients with lower limb spasticity and positive family history in order to help to establish the correct diagnosis.

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