scholarly journals Autosomal Recessive Oculodentodigital Dysplasia: A Case Report and Review of the Literature

2018 ◽  
Vol 154 (4) ◽  
pp. 181-186 ◽  
Author(s):  
Elifcan Taşdelen ◽  
Ceren D. Durmaz ◽  
Halil G. Karabulut
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Rare Condition ◽  
Clinical Findings ◽  
Homozygous Mutation ◽  
Nasal Bridge ◽  
Oculodentodigital Dysplasia ◽  
Autosomal Recessive Manner

Oculodentodigital dysplasia (ODDD) is a rare condition characterized by a typical facial appearance and variable findings of the eyes, teeth, and fingers. ODDD is caused by mutations in the GJA1 gene in chromosome 6q22 and inherited in an autosomal dominant manner in the majority of the patients. However, in recent clinical reports, autosomal recessive ODDD cases due to by GJA1 mutations were also described. Here, we report on a 14-year-old boy with microphthalmia, microcornea, narrow nasal bridge, hypoplastic alae nasi, prominent columnella, hypodontia, dental caries, and partial syndactyly of the 2nd and 3rd toes. These clinical findings were concordant with the diagnosis of ODDD, and a novel homozygous mutation (c.442C>T, p.Arg148Ter) was determined in the GJA1 gene leading to a premature stop codon. His phenotypically normal parents were found to be carriers of the same mutation. This is the third family in the literature in which ODDD segregates in an autosomal recessive manner.

An Autosomal-Recessive GFI1B Mutation Defines the Splice Isoform p37 As Essential for Biogenesis of Functional Human Platelets, but Dispensable for Erythropoiesis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2644-2644
Author(s):  
Harald Schulze ◽  
Axel Schlagenhauf ◽  
Georgi Manukjan ◽  
Christine Beham-Schmid ◽  
Oliver Andres ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Growth Factor ◽  
Autosomal Recessive ◽  
Stop Codon ◽  
Zinc Fingers ◽  
Premature Stop Codon ◽  
Index Patient ◽  
Homozygous Mutation ◽  
Recessive Trait ◽  
Erythroid Progenitor

Abstract Growth factor independent 1 (GFI1) and Growth Factor Independent 1B (GFI1B) are zinc finger transcriptional repressors that share about 90% homology on amino acid sequence and are expressed during hematopoiesis. While GFI1 is most important for granulocyte-monocyte lineage commitment, GFI1B is an essential master regulator of erythroid and megakaryocytic lineages. Mice lacking Gfi1b are embryonic lethal due to anemia and thrombocytopenia. In humans, alternative splicing leads to a shorter p32 isoform that lacks the first 2 of 6 zinc fingers. GFI1B germline mutations have been reported to cause autosomal-dominant macrothrombocytopenia with a grey-platelet syndrome phenotype, implying that the mutant protein acts in a dominant-negative manner. We report on a Chechen family from eastern Georgia whose affected family members all present with severe, life-threatening bleeding diathesis. The female index patient had recurrent hematomata and multiple petechiae since childhood. Both of her children (age 9 and 7) present with very low platelet counts (below 45/nL) and a similar cutaneous bleeding pattern like her mother. The brother also had thrombocytopenia and died at age 33 in reponse to a spontaneous cerebral hemorrhage. In contrast, the index patient's husband, her parents and the children of the deceased brother were clinically unaffected. Blood smears of affected patients showed macrothrombocytopenia with reduced May-Grünwald-Giema staining and decreased staining for alpha-granule markers von Willebrand factor (vWF) and P-selectin (CD62P). Platelet function testing revealed reduced responses to ADP, collagen, TRAP-6 and arachidonic acid. White and red blood cell parameters were overall normal in the index patient and the two affected children. We analyzed DNA from the index patient by targeted next generation sequencing for 59 genes relevant for platelet formation or function. We found a novel homozygous single nucleotide insertion in GFI1B (NM_004188.5; c.551insG), which was confirmed by Sanger sequencing and is expected to cause a premature stop-codon. The homozygous mutation co-segregated with the phenotype. The unaffected mother, the husband and two unaffected nephews were heterozygous, suggesting a local founder variant and an unexpected autosomal-recessive trait. Bone marrow analysis showed unaffected myeloid and erythroid cells, but dysplastic micromegakaryocytes with increased CD34 staining. Peripheral blood platelets were also positive for CD34. We performed quantitative real-time PCR of platelet RNA and found residual homozygous c.551_G insertion in the p37 transcript and an unexpected expression of the p32 variant. The p37 transcript was markedly reduced in context with an increased p32/p37 ratio compared to controls. Our findings indicate that the mutated transcript was not completely degraded by nonsense-mediated decay, but mostly subjected to alternative splicing skipping the mutated exon 9. Our findings imply that the first two zinc fingers of GFI1B are dispensable for human erythropoiesis, but essential for normal megakaryopoiesis and the production of functional platelets. While previous mutations affect both isoforms, the insertion variant presented here, results in a premature stop-codon and affects only the p37 isoform due to alternative splicing. This splice variant defines an important node at the megakaryocytic-erythroid progenitor stage and we conclude that the transcriptional regulation of erythropoiesis is uncoupled from that of megakaryopoiesis through alternative splicing of GFI1B. Disclosures No relevant conflicts of interest to declare.

scholarly journals SUN-275 A Rare Mutation in the TBX19 Gene Leading to Isolated ACTH Deficiency in Two Siblings

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Norbert Albers ◽  
Amelie Bartels ◽  
Renate Peters ◽  
Jens Banzer
Keyword(s):  
Genetic Analysis ◽  
Neonatal Period ◽  
Stop Codon ◽  
Correct Diagnosis ◽  
Premature Stop Codon ◽  
Rare Condition ◽  
Homozygous Mutation ◽  
Upper Respiratory Tract ◽  
Isolated Acth Deficiency ◽  
Acth Deficiency

Abstract Hypoglycemia and hyperammonemia (>500µg/dl) in a newborn led to the suspicion of THAN (transient hyperammonemia of the newborn). Subsequently, hypoglycemic and salt losing episodes with low cortisol (<0,1 ug/dl) and ACTH (<0,16 pg/ml) levels pointed to ACTH deficiency. Genetic analysis showed a homozygous mutation c.302G>A for p.(Trp101*) in the TBX19 gene (a positive regulator of the transcription of POMC and the terminal differentiation of the corticotrophs), generating a premature stop codon. This mutation has been described only once and very recently by Abali et al (Hormones 18:229; 2019) in a 4 year old girl, but unlike our patients, this girl was obviously unaffected during her neonatal period. All other pituitary axes in our patient were normal, thus congenital isolated ACTH deficiency was the final diagnosis. Hyperammonemia resolved spontaneously and the suspected diagnosis of THAN could be dismissed. Hyperammonemia had probably been due to metabolic stress.After 16 months, a younger brother was born and showed hypoglycemia, hypotension and respiratory infection during his neonatal period. Cortisol and ACTH levels were also very low, thereafter, the same TBX19 mutation was detected.Both brothers were successfully treated with oral hydrocortisone substitution (6–10 mg/sqm/day q8 with increases during stress) and thrive well, except for several infections of the upper respiratory tract in the younger brother. In summary, we report the very rare condition of familial isolated congenital ACTH deficiency with a mutation of TBX19 that has never been described in newborns. Initial presentation may be accompanied by confounding pathological lab findings, while genetic analysis together with extremely low ACTH and cortisol levels confirm the correct diagnosis.

scholarly journals Genetic testing for ocular coloboma

2017 ◽  
Vol 1 (s1) ◽  
pp. 29-31 ◽  
Author(s):  
Andi Abeshi ◽  
Carla Marinelli ◽  
Tommaso Beccari ◽  
Munis Dundar ◽  
Leonardo Colombo ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Clinical Utility ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Scientific Literature ◽  
Genetic Test ◽  
Clinical Findings ◽  
Fundus Examination ◽  
Live Births ◽  
Autosomal Recessive Manner

Abstract We studied the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for ocular coloboma (COI). COI is inherited in an autosomal dominant manner associated with variations in the PAX6, ABCB6 and FZD5 genes and in an autosomal recessive manner associated with variations in the SALL2 gene. Overall prevalence is 1 per 100,000 live births. Clinical diagnosis is based on clinical findings, ophthalmogical examination, family history, fundus examination and electroretinography. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.

scholarly journals Genetic testing for non syndromic retinitis pigmentosa

2017 ◽  
Vol 1 (s1) ◽  
pp. 92-95
Author(s):  
Andi Abeshi ◽  
Alice Bruson ◽  
Tommaso Beccari ◽  
Munis Dundar ◽  
Fabiana D’Esposito ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Retinitis Pigmentosa ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Fundus Autofluorescence ◽  
Clinical Findings ◽  
Ophthalmological Examination ◽  
Corrected Visual Acuity ◽  
Recessive Transmission ◽  
Autosomal Recessive Manner

Abstract We reviewed the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for non syndromic retinitis pigmentosa (NSRP). NSRP is determined by variations in the ABCA4, AGBL5, ARL2BP, ARL6, BBS2, BEST1, C2orf71, C8orf37, CA4, CDHR1, CERKL, CLRN1, CNGA1, CNGB1, CRB1, CRX, DHDDS, EYS, FAM161A, FSCN2, GUCA1B, HGSNAT, IDH3B, IFT140, IFT172, IMPDH1, IMPG2, KIZ, KLHL7, LRAT, MAK, MERTK, NEK2, NR2E3, NRL, OFD1, PDE6A, PDE6B, PDE6G, POMGNT1, PRCD, PROM1, PRPF3, PRPF31, PRPF4, PRPF6, PRPF8, PRPH2, RBP3, RDH12, RGR, RHO, RLBP1, ROM1, RP1, RP2, RP9, RPE65, RPGR, SAG, SEMA4A, SLC7A14, SNRNP200, SPATA7, TOPORS, TTC8, TULP1, USH2A, ZNF408 and ZNF513 genes. Its overall prevalence is 1 per 4000. It is mostly inherited in an autosomal recessive manner, fewer genes have autosomal dominant or X-linked recessive transmission. Clinical diagnosis is based on clinical findings, ophthalmological examination, best corrected visual acuity (BCVA), slit lamp biomicroscopy, fundus autofluorescence, electroretinography, color vision testing and optical coherence tomography. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.

scholarly journals Mutation in the RPE65 gene causing hereditary retinal dystrophy in the Briard dogs: application of a new detection method

2008 ◽  
Vol 53 (No. 4) ◽  
pp. 176-179
Author(s):  
R. Bechyňová ◽  
J. Dostál ◽  
A. Stratil ◽  
F. Jílek ◽  
P. Horák
Keyword(s):  
Autosomal Recessive ◽  
Clinical Symptoms ◽  
Stop Codon ◽  
Retinal Dystrophy ◽  
Premature Stop Codon ◽  
Causative Mutation ◽  
Functional Protein ◽  
Hereditary Retinal Dystrophy ◽  
Briard Dogs ◽  
Autosomal Recessive Manner

Inherited eye diseases are widespread in most of the pure dog breeds and they show a severe impact on canine health, welfare and working ability. Congenital stationary night blindness (CSNB) was originally described in Briards. CSNB is slow progressive retinal degeneration with very early onset of clinical symptoms and is inherited in an autosomal recessive manner. The causative mutation (Y16567.1:c.487_490delAAGA) for CSNB was identified in exon 5 of the <I>RPE6</I>5 gene. This deletion results in a frameshift and leads to a premature stop codon and expression of a non-functional protein. To date, only expensive, laborious or unpractical methods have been used for detection of the mutation in the canine <I>RPE65</I> gene. The main goals of this study were to develop a new method for routine genotyping of the causative mutation and to assess its occurrence in the Czech population of Briards. The method of electrophoresis in the gel Spraedex EL600 can be widely used for genotyping of the <I>RPE65</I> gene as a basis of proper genetic counselling and an improvement of genetic health in the Briard populations. In the studied population, the following frequencies of alleles + (wild) and – (mutant) were observed – 0.939 and 0.061, respectively.

scholarly journals Genetic testing for optic atrophy

2017 ◽  
Vol 1 (s1) ◽  
pp. 83-85
Author(s):  
Andi Abeshi ◽  
Alice Bruson ◽  
Tommaso Beccari ◽  
Munis Dundar ◽  
Benedetto Falsini ◽  
...  
Keyword(s):  
Optic Atrophy ◽  
Clinical Utility ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Scientific Literature ◽  
Genetic Test ◽  
Clinical Findings ◽  
Ophthalmological Examination ◽  
Live Births ◽  
Autosomal Recessive Manner

Abstract We studied the scientific literature and disease guidelines in order to summarize the clinical utility of the genetic test for optic atrophy (OA). OA is mostly inherited in an autosomal dominant manner, rarely in an autosomal recessive manner, with an overall prevalence of 3/100,000 live births. It is caused by mutations in the OPA1, OPA3 and TMEM126A genes. Clinical diagnosis is based on clinical findings, ophthalmological examination, OCT, visual evoked potentials (VEPs) and electroretinography. The genetic test is useful for confirming diagnosis, differential diagnosis, couple risk assessment and access to clinical trials.

scholarly journals Genetic testing for congenital stationary night blindness

2017 ◽  
Vol 1 (s1) ◽  
pp. 38-40
Author(s):  
Andi Abeshi ◽  
Pamela Coppola ◽  
Tommaso Beccari ◽  
Munis Dundar ◽  
Francesco Viola ◽  
...  
Keyword(s):  
Clinical Utility ◽  
Night Blindness ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Scientific Literature ◽  
Genetic Test ◽  
Clinical Findings ◽  
Ophthalmological Examination ◽  
Congenital Stationary Night Blindness ◽  
Autosomal Recessive Manner

Abstract We studied the scientific literature and disease guidelines in order to summarize the clinical utility of the genetic test for congenital stationary night blindness (CSNB). CSNB is inherited in an autosomal dominant manner in the case of mutations in the GNAT1, PDE6B and RHO genes, in an autosomal recessive manner in the case of mutations in the CABP4, GNB3, GPR179, GRM6, LRIT3, SAG, SLC24A1, TRPM1 and genes and in an X-linked recessive manner in the case of mutations in the CACNA1F and NYX genes. The overall prevalence of CSNB is not known. Clinical diagnosis is based on clinical findings, ophthalmological examination, visual evoked potentials and electroretinography. The genetic test is useful for confirming diagnosis and for differential diagnosis, couple risk assessment and access to clinical trials.

scholarly journals Genetic testing for Mendelian myopia

2017 ◽  
Vol 1 (s1) ◽  
pp. 74-76
Author(s):  
Andi Abeshi ◽  
Pamela Coppola ◽  
Tommaso Beccari ◽  
Munis Dundar ◽  
Leonardo Colombo ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Genetic Testing ◽  
Clinical Utility ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Scientific Literature ◽  
Genetic Test ◽  
Clinical Findings ◽  
Ophthalmological Examination ◽  
Recessive Transmission

Abstract We studied the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for Mendelian myopia (MM), a large and heterogeneous group of inherited refraction disorders. Variations in the SLC39A5, SCO2 and COL2A1 genes have an autosomal dominant transmission, whereas those in the LRPAP1, P3H2, LRP2 and SLITRK6 genes have autosomal recessive transmission. The prevalence of MM is currently unknown. Clinical diagnosis is based on clinical findings, family history, ophthalmological examination and other tests depending on complications. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.

Novel integrin-dependent platelet malfunction in siblings with leukocyte adhesion deficiency-III (LAD-III) caused by a point mutation in FERMT3

2010 ◽  
Vol 103 (05) ◽  
pp. 1053-1064 ◽  
Author(s):  
Kerstin Jurk ◽  
Ansgar Schulz ◽  
Beate Kehrel ◽  
Daniel Räpple ◽  
Harald Schulze ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Stop Codon ◽  
Leukocyte Adhesion ◽  
Premature Stop Codon ◽  
Homozygous Mutation ◽  
Leukocyte Adhesion Deficiency ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Granule Secretion ◽  
Focal Adhesion Protein

SummaryLeukocyte adhesion deficiency-III (LAD-III) also called leukocyte adhesion deficiency-1/variant (LAD1v) is a rare congenital disease caused by defective integrin activation of leukocytes and platelets. Patients with LAD-III present with non-purulent infections and increased bleeding symptoms. We report on a novel integrin-dependent platelet dys-function in two brothers with LAD-III syndrome caused by a homozygous mutation 1717C>T in the FERMT3 gene leading to a premature stop codon R573X in the focal adhesion protein kindlin-3. Stimulation of patients´ platelets with all used agonists resulted in a severely decreased binding of soluble fibrinogen indicating a defect in inside-out activation of the integrin αIIbβ3 (GPIIb/IIIa). Patients´ platelets did not respond to the α2β1-integrin agonist aggretin-A at all. Our data on granula secretion indicate for the first time that the thrombin receptor PAR-4 but not PAR-1 may be important in integrin-triggered granule secretion in response to thrombin. In contrast, collagen mediated platelet granule secretion was not affected in LAD-III-patients. Thus, integrin-signalling may be not essential in collagen-induced granule secretion. The patients’ peripheral blood mononuclear cells showed a severe loss of adhesion capacity to VCAM-1 and to endothelial cells compared to cells from healthy donors. Rap-1 activation after PMA stimulation could be observed in controls´ but not in patients´ cells. After haematogenesis stem cell transplantation (HSCT) the brothers showed no symptoms of bleeding or immunodeficiency and the integrin-dependent platelet and leukocyte functions normalised.

scholarly journals Premature Stop Codon in MMP20 Causing Amelogenesis Imperfecta

2008 ◽  
Vol 87 (1) ◽  
pp. 56-59 ◽  
Author(s):  
P. Papagerakis ◽  
H.-K. Lin ◽  
K.Y. Lee ◽  
Y. Hu ◽  
J.P. Simmer ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Proteolytic Enzymes ◽  
Stop Codon ◽  
Translation Termination ◽  
Premature Stop Codon ◽  
Dental Enamel ◽  
Amino Acid Position ◽  
Amelogenesis Imperfecta ◽  
Exon 1 ◽  
Kallikrein 4

Proteolytic enzymes are necessary for the mineralization of dental enamel during development, and mutations in the kallikrein 4 ( KLK4) and enamelysin ( MMP20) genes cause autosomal-recessive amelogenesis imperfecta (ARAI). So far, only one KLK4 and two MMP20 mutations have been reported. We have identified an ARAI-causing point mutation (c.102G>A, g.102G>A, and p.W34X) in exon 1 of MMP20 in a proband with autosomal-recessive hypoplastic-hypomaturation amelogenesis imperfecta. The G to A transition changes the tryptophan (W) codon (TGG) at amino acid position 34 into a translation termination (X) codon (TGA). No disease-causing sequence variations were detected in KLK4. The affected enamel is thin, with mild spacing in the anterior dentition. The enamel layer is hypomineralized, does not contrast with dentin on radiographs, and tends to chip away from the underlying dentin. An intrinsic yellowish pigmentation is evident, even during eruption. The phenotype supports current ideas concerning the function of enamelysin.

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