scholarly journals Variant Analysis of Alkaptonuria Families with Significant Founder Effect in Jordan

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Raida Khalil ◽  
Dema Ali ◽  
Nesrin Mwafi ◽  
Arwa Alsaraireh ◽  
Loiy Obeidat ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Family Members ◽  
Autosomal Recessive Disorder ◽  
Missense Variant ◽  
Homogentisic Acid ◽  
Common Variants ◽  
Genetic Features ◽  
Heterozygous Carriers ◽  
Variant Analysis ◽  
Age Range

Background. Metabolic disorder alkaptonuria is an autosomal recessive disorder caused by mutations in the HGD gene, and a deficiency HGD enzyme activity results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue. Methods. We clinically evaluated 18 alkaptonuria patients (age range, 3 to 60 years) from four unrelated families. Furthermore, 11 out of 18 alkaptonuria patients and 7 unaffected members were enrolled for molecular investigations by utilizing Sanger sequencing to identify variants of the 14 exons of HGD gene. Results. We found that the seven patients from the 4 unrelated families carried a recurrent pathogenic missense variant (c.365C>T, p. Ala122Val) in exon 6 of HGD gene. The variant was fully segregated with the disease in affected family members while the other unaffected family members were heterozygous carriers for this variant. Additionally, the clinical features were fully predicted with alkaptonuria disorder. Conclusion. In this study, we confirmed that the most common variants in Jordanian AKU patients was c.365C>T, p. Ala122Val in exon 6 of HGD gene. Additionally, we correlated the clinical and genetic features of AKU patients at various ages (3-60 years).

scholarly journals Spondylocarpotarsal synostosis syndrome due to a novel loss of function FLNB variant: a case report

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Samina Yasin ◽  
Outi Makitie ◽  
Sadaf Naz
Keyword(s):  
Short Stature ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Loss Of Function ◽  
Case Presentation ◽  
Pathogenic Variants ◽  
Skeletal Malformations ◽  
Tarsal Bones ◽  
The Family ◽  
Heterozygous Carriers

Abstract Background Loss of function or gain of function variants of Filamin B (FLNB) cause recessive or dominant skeletal disorders respectively. Spondylocarpotarsal synostosis syndrome (SCT) is a rare autosomal recessive disorder characterized by short stature, fused vertebrae and fusion of carpal and tarsal bones. We present a novel FLNB homozygous pathogenic variant and present a carrier of the variant with short height. Case presentation We describe a family with five patients affected with skeletal malformations, short stature and vertebral deformities. Exome sequencing revealed a novel homozygous frameshift variant c.2911dupG p.(Ala971GlyfsTer122) in FLNB, segregating with the phenotype in the family. The variant was absent in public databases and 100 ethnically matched control chromosomes. One of the heterozygous carriers of the variant had short stature. Conclusion Our report expands the genetic spectrum of FLNB pathogenic variants. It also indicates a need to assess the heights of other carriers of FLNB recessive variants to explore a possible role in idiopathic short stature.

scholarly journals Warmblood fragile foal syndrome causative single nucleotide polymorphism frequency in horses in Ireland

2021 ◽  
Vol 74 (1) ◽  
Author(s):  
Áine Rowe ◽  
Sharon Flanagan ◽  
Gerald Barry ◽  
Lisa M. Katz ◽  
Elizabeth A. Lane ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Scientific Literature ◽  
Genetic Test ◽  
Low Frequency ◽  
Autosomal Recessive Disorder ◽  
Causative Mutation ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Hair Samples ◽  
Heterozygous Carriers

Abstract Background Warmblood Fragile Foal Syndrome (WFFS) is an autosomal recessive disorder caused by a mutation in the procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) gene. Homozygosity for the mutation results in defective collagen synthesis which clinically manifests as the birth of non viable or still born foals with abnormally fragile skin. While the mutation has been identified in non Warmblood breeds including the Thoroughbred, to date all homozygous clinically affected cases reported in the scientific literature are Warmblood foals. The objective of this study was to investigate the carrier frequency of the mutation in the Thoroughbred and sport horse populations in Ireland. Methods A test was developed at the UCD School of Veterinary Medicine using real-time PCR to amplify the PLOD1 gene c.2032G > A variant. A subset of the samples was also submitted to an external laboratory with a licensed commercial WFFS genetic test. Results Warmblood Fragile Foal Syndrome genotyping was performed on hair samples from 469 horses representing 6 different breeds. Six of 303 (1.98%) sport horses tested and three of 109 (2.75%) Thoroughbreds tested were heterozygous for the WFFS polymorphism (N/WFFS). The WFFS polymorphism was not identified in the Standardbred, Cob, Connemara, or other pony breeds. Conclusions The study identified a low frequency of the WFFS causative mutation in sport horses and Thoroughbreds in Ireland, highlighting the importance of WFFS genetic testing in order to identify phenotypically normal heterozygous carriers and to prevent the birth of nonviable foals.

Alkaptonuria: clinical manifestations and an updated approach to treatment of a rare disease

2021 ◽  
Vol 14 (12) ◽  
pp. e244240
Author(s):  
Ryan Curtis Roopnarinesingh ◽  
Noel Edward Donlon ◽  
John V Reynolds
Keyword(s):  
Rare Disease ◽  
Enzymatic Degradation ◽  
Autosomal Recessive ◽  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Cartilage Destruction ◽  
Homogentisic Acid ◽  
Connective Tissues ◽  
Tendon Ruptures ◽  
Published Research

Alkaptonuria (AKU) is a rare autosomal recessive disorder with a global incidence of 1 in 250 000 to 1 million people worldwide. It results from a deficiency of the enzyme homogentisic acid (HGA) oxidase which when absent, leads to an accumulation of HGA. Without this enzymatic degradation, HGA deposits in connective tissues resulting in pigmentation (ochronosis), plaque formation and accelerated cartilage destruction. With this, many patients who suffer from AKU develop ochronotic arthropathies, tendon ruptures, fractures, and chronic joint pain. Similarly, patients can develop cardiac valvular dysfunction and interstitial renal disease. Our two cases highlight the array of pathologies seen in AKU and, in light of newly published research, give us a platform from which we can discuss the developments in management of this rare disease.

3-M syndrome – a primordial short stature disorder with novel CUL7 mutation in two Indian patients

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Radha Rama Devi Akella
Keyword(s):  
Short Stature ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Autosomal Recessive Disorder ◽  
Missense Variant ◽  
Postnatal Growth ◽  
Compound Heterozygous ◽  
Case Presentation ◽  
Whole Exome ◽  
Heterozygous Variant

Abstract Objective To evaluate the cause of short stature in children. Case presentation Two children with suspected skeletal dysplasia and short stature were evaluated. Conclusions The 3-M syndrome is a primordial growth disorder manifesting severe postnatal growth restriction, skeletal anomalies and prominent fleshy heels. The 3-M syndrome is a genetically heterogeneous disorder and the phenotype is similar. This is a rare autosomal recessive disorder with normal intellect. Two affected children have been identified by whole-exome sequencing. One patient harboured a compound heterozygous variant and the other was a homozygous missense variant. The genetic diagnosis helped in counselling the families and facilitated prenatal diagnosis in one (case 1) family.

scholarly journals Alkaptonuria

2017 ◽  
Vol 49 (1-2) ◽  
pp. 37-39
Author(s):  
Md Nazrul Islam ◽  
SM Kamal ◽  
Sk Amir Hossain ◽  
Sirajul Islam
Keyword(s):  
Back Pain ◽  
Male Patient ◽  
Joint Pain ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Homogentisic Acid ◽  
Multiple Nodules

Alkaptonuria is a rare metabolic autosomal recessive disorder. It occurs due to lack of an enzyme that results in deposition of homogentisic acid in various tissues. A male patient of 45 years presented with back pain for 20 years and multiple joint pain for 10 years. Patient has multiple nodules in both pinnae and pigmentation in both sclerae. His urine turns black upon standing. These findings are compatible with the diagnosis of Alkaptonuria.Bang Med J (Khulna) 2016; 49 : 37-39

scholarly journals SPONTANEOUS ACHILLES TENDON RUPTURE - A CASE OF OCHRONOSIS

2013 ◽  
Vol 03 (03) ◽  
pp. 113-115 ◽  
Author(s):  
Sanath Kumar Shetty ◽  
Raj Sankar N. R. ◽  
Nirmal Babu P. ◽  
Lawrence J. Mathias ◽  
Shubha P. Bhat ◽  
...  
Keyword(s):  
Achilles Tendon ◽  
Spontaneous Rupture ◽  
Autosomal Recessive ◽  
Tendon Rupture ◽  
Achilles Tendon Rupture ◽  
Autosomal Recessive Disorder ◽  
Intervertebral Discs ◽  
Homogentisic Acid ◽  
Acid Oxidase ◽  
Articular Cartilages

AbstractAlkaptonuria is a rare autosomal recessive disorder characterised by the absence of homogentisic acid oxidase and the subsequent accumulation of homogentisic acid, a metabolic product of the aromatic aminoacids phenylalanine and tyrosine; which is deposited in articular cartilages, intervertebral discs, sclera, tympanic membrane, tendons and ligaments leading to their degeneration. Here we describe a case of spontaneous rupture of Achilles tendon1,2,3 due to Ochronosis.

Importance of Immediate Thiamine Therapy in Children with Suspected Thiamine-Responsive Megaloblastic Anemia—Report on Two Patients Carrying a Novel SLC19A2 Gene Mutation

2020 ◽  
Author(s):  
Anita Spehar Uroic ◽  
Dragan Milenkovic ◽  
Elisa De Franco ◽  
Ernest Bilic ◽  
Natasa Rojnic Putarek ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Autosomal Recessive ◽  
Megaloblastic Anemia ◽  
Sensorineural Deafness ◽  
Autosomal Recessive Disorder ◽  
Missense Variant ◽  
Severe Anemia ◽  
Thiamine Therapy ◽  
Compound Heterozygotes ◽  
Slc19a2 Gene

AbstractThiamine-responsive megaloblastic anemia (TRMA) is an autosomal recessive disorder characterized by the development of megaloblastic anemia, diabetes mellitus, and sensorineural deafness. We report on the first two Croatian patients with TRMA, compound heterozygotes for nonsense, c.373C > T; p.(Gln125Ter) and novel missense variant, c.1214C > G; p.(Thr405Arg) in SLC19A2 gene. The first was diagnosed at 4 months with diabetes mellitus and severe anemia requiring transfusions. As TRMA was suspected, thiamine therapy was immediately started to prevent further transfusions and insulin therapy. His brother developed extreme anemia at 3 weeks of age while waiting for the results of the genetic test. Severe anemia in this sibling may have been prevented if thiamine had been initiated earlier.

scholarly journals FIG4-Associated Yunis-Varon Syndrome: Identification of a Novel Missense Variant

2021 ◽  
pp. 1-7
Author(s):  
Muhammad Umair ◽  
Turki M. Alkharfy ◽  
Sajida Sajjad ◽  
Majid Alfadhel
Keyword(s):  
Skeletal Muscles ◽  
Autosomal Recessive ◽  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Missense Variant ◽  
Cleidocranial Dysplasia ◽  
Gene Encoding ◽  
Phosphoinositide Phosphatase ◽  
Whole Exome ◽  
Poor Outcomes

Yunis-Varon syndrome (YVS; OMIM 216340) is a rare heterogeneous autosomal recessive disorder with easy recognition of characteristic severe neurological and skeletal abnormalities involving skeletal muscles and cartilages. This cleidocranial dysplasia is characterized by bone and tooth disorders; it also affects the cardiovascular system and tissues from ectoderm with very poor outcomes. Rarely, mutations of the <i>FIG4</i> gene, encoding a 50-phosphoinositide phosphatase have been identified as the cause for YVS. We report a neonate born to a consanguineous couple with typical clinical manifestations of YVS. Using whole-exome sequencing, we identified a novel homozygous missense variant (c.968A&#x3e;G; p.Gln323Arg) in the <i>FIG4</i> gene. Thus, our study expands the molecular and genetic spectrum of <i>FIG4</i>-associated mutations. To our knowledge, this is the first reported case of YVS from the Saudi population.

A large Swiss family with Bernard-Soulier syndrome

2009 ◽  
Vol 29 (02) ◽  
pp. 161-167 ◽  
Author(s):  
B. Zieger ◽  
A. Jenny ◽  
D. A. Tsakiris ◽  
I. Bartsch ◽  
K. Sandrock ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Fragment Length Polymorphism ◽  
Family Members ◽  
Genetic Alterations ◽  
Platelet Volume ◽  
Giant Platelets ◽  
Two Generations ◽  
Heterozygous Carriers ◽  
Restriction Fragment Length ◽  
Bernard Soulier Syndrome

SummaryBernard-Soulier syndrome (BSS) is a rare, autosomal recessive inherited bleeding disorder associated with thrombocytopenia, thrombocytopathy and giant platelets. BSS is caused by genetic alterations of the glycoprotein (GP) Ib/V/IX complex.We report on a large Swiss family of whom four family members suffer from BSS. Here, a homozygous missense mutation in position 1829 (A→G) of the GPIX gene constituting a N45S substitution is the cause for the bleeding symptoms. A totalof 38 family members within two generations were analyzed regarding the N45S mutation by DNA sequencing and restriction fragment length polymorphism. The laboratory parameters which are characteristically for BSS such as platelet count, platelet volume and the expression of CD42a (GPIX), CD42b (GPIbα) and CD41 (GPIIb) were measured for all 38 individuals. The four homozygous patients showed bleeding symptoms, thrombocytopenia and giant platelets. In these patients, the expression of CD42a (GPIX), CD42b (GPIbα) was diminished. Interestingly, the intensity of the bleeding symptoms of the 4 homozygous family members seemed to vary although they carry the same mutation. The 24 heterozygous carriers did not differ significantly from their 10 wildtype family members regarding bleeding symptoms and laboratory analysis.

Specific Cognitive Changes due to Hippocalcin Alterations? A Novel Familial Homozygous Hippocalcin Variant Associated with Inherited Dystonia and Altered Cognition

2021 ◽  
Author(s):  
Sandy Siegert ◽  
Wolfgang M. Schmidt ◽  
Thomas Pletschko ◽  
Reginald E. Bittner ◽  
Sonja Gobara ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Pediatric Patient ◽  
Autosomal Recessive ◽  
Family Members ◽  
Missense Variant ◽  
Index Patient ◽  
Cognitive Changes ◽  
Her Family ◽  
Whole Exome

Abstract Background Recent research suggested an hippocalcin (HPCA)-related form of DYT2-like autosomal recessive dystonia. Two reports highlight a broad spectrum of the clinical phenotype. Here, we describe a novel HPCA gene variant in a pediatric patient and two affected relatives. Methods Whole exome sequencing was applied after a thorough clinical and neurological examination of the index patient and her family members. Results of neuropsychological testing were analyzed. Results Whole exome sequencing revealed a novel homozygous missense variant in the HPCA gene [c.182C>T p.(Ala61Val)] in our pediatric patient and the two affected family members. Clinically, the cases presented with dystonia, dysarthria, and jerky movements. We observed a particular cognitive profile with executive dysfunctions in our patient, which corresponds to the cognitive deficits that have been observed in the patients previously described. Conclusion We present a novel genetic variant of the HPCA gene associated with autosomal recessive dystonia in a child with childhood-onset dystonia supporting its clinical features. Furthermore, we propose specific HPCA-related cognitive changes in homozygous carriers, underlining the importance of undertaking a systematic assessment of cognition in HPCA-related dystonia.

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