Abstract: The clinical effect of T118M variant of the PMP22 gene has been controversial. Several studies have suggested that it may be autosomal recessive, partial loss of function, or a benign variant. Here we report three cases in further support that the T118M variant of the PMP22 gene is a partial loss of function variant. These three unrelated cases were heterozygotes with the T118M variant of the PMP22 gene. All three cases presented with painful peripheral neuropathy and varying degrees of Charcot-Marie-Tooth exam features. Electrophysiological studies revealed polyneuropathy with axonal and demyelinating features in one case, but there were minimal electrophysiological changes in the other two cases. We propose that the T118M variant can cause painful peripheral neuropathy, which may be an underrecognized feature of this variant. PubDate: Tue, 25 Dec 2018 05:54:24 +000
Abstract: Hereditary sensory and autonomic neuropathies (HSANs) are a clinically and genetically heterogeneous group of disorders involving various sensory and autonomic dysfunctions. The most common symptoms of HSANs include loss of sensations of pain and temperature that frequently lead to chronic ulcerations in the feet and hands of the patient. In this case study, we present the clinical features and genetic characteristics of two affected individuals from two unrelated Saudi families presenting mutilating sensory loss and spastic paraplegia. We employed homozygosity mapping and exome sequencing which is an efficient strategy to characterize the recessive genes, thus obtaining a rapid molecular diagnosis for genetically heterogeneous disorders like HSAN. Subsequently, a nonsense mutation (c.926 C>G; p.S309) in FAM134B was identified. In addition, we confirmed that the mutant FAM134B transcripts were reduced in these patients presumably disrupting the receptors of the degradative endoplasmic reticulum pathways that facilitate the autophagy processes. PubDate: Wed, 12 Dec 2018 00:00:00 +000
Abstract: GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder due to mutations in the lysosomal acid 3-galactosidase gene, GLB1. It is usually classified into three forms, infantile, juvenile, or adult, based on age at onset and severity of central nervous system involvement. Because of their broad clinical spectrum and their similarity to many other aetiologies, including inherited neurodegenerative and metabolic diseases, it is often difficult to diagnose such diseases. Recently, whole exome sequencing (WES) has become increasingly used when a strong hypothesis cannot be formulated based on the clinical phenotype. Here, we present three patients belonging to a consanguineous Moroccan family with a GM1-gangliosidosis with unusual clinical onset and atypical radiological presentation that had eluded diagnosis for over a decade. To identify the disease-causing mutation, we performed a whole exome sequencing and a chromosomal microarray genotyping in order to reduce the number of genetic variants to be interpreted, by focusing the data analysis only on the linked loci. The already known pathogenic missense mutation c.601G>A in GLB1 (p.R201C) was found at homozygous state in the proband V.1 and at heterozygous state in his father IV.1. The mutation was validated by Sanger sequencing and segregated in all the family members according to a recessive mode of inheritance. Outside of the linked loci, we found the EXOSC8 p.Ser272Thr mutation at heterozygous state in all the patients and their mother IV.2. This mutation was reported to cause pontocerebellar hypoplasia type 1C and could act as a modifying factor that exacerbates the brain atrophy of patients. Our study identified the first GLB1 mutation in North Africa in patients with unexpected brain-MRI outcomes extending the clinical spectrum of the GM1-gangliosidosis. PubDate: Thu, 15 Nov 2018 00:00:00 +000
Abstract: Background. Birt-Hogg-Dubé syndrome is a genetic disorder characterized by skin fibrofolliculomas, cystic lung disease, and bilateral renal tumors. It has also been implicated in the formation of tumors in other organs, particularly thyroid and colon. This case presents a young female presenting with only cystic lung disease and kidney tumors, identified as having a never before identified heterozygous mutation in the folliculin (FLCN) gene which is the likely cause of her syndrome. Case Presentation. A 34-year-old female was found to have bilateral renal masses, 2.4 cm on the right and 7.6 cm on the left, as well as multiple, small cysts in the lungs. Chest imaging further characterized the lung cysts as being basilar predominant with the largest measuring 1.6cm. The left kidney mass was resected with a partial nephrectomy with final pathologic diagnosis of an oncocytoma. Genetic testing was undertaken as she did not have characteristic skin findings. A previously undescribed mutation in the FLCN gene (c.780-2A>G) was identified with no matches in the human genetic mutation database (HGMD). Review of that database identified over 160 separate mutations in the FLCN gene. Extensive history did not identify any family members who had similar disease processes suggesting that this could be a spontaneous mutation in the proband. Conclusions. This case highlights that the traditional view of Birt-Hogg-Dubé syndrome as having a strong familial component may be incorrect and that spontaneous mutation may be more common than previously thought. Also notable is the fact that this patient had no characteristically described fibrofolliculomas that traditionally are the hallmark of the condition. This case suggests that genetic testing should be obtained in all suspected cases of Birt-Hogg-Dubé syndrome as the patient may not present with the typical skin findings and may also present with no family history consistent with this disorder. PubDate: Wed, 07 Nov 2018 06:45:13 +000
Abstract: Individuals with Sickle Cell Trait (SCT), generally considered a benign carrier state of hemoglobin S (HbAS), are thought to be at risk for exertional rhabdomyolysis and hematuria, conditions that can also be caused by various other acquired and inherited factors. We report an SCT positive service member with an exertional rhabdomyolysis event, recurrent hematuria with transient proteinuria, and episodic burning pain in the lower extremities. Clinical and genetic studies revealed the multifactorial nature of his complex phenotype. The service member was taking prescription medications known to be associated with exertional rhabdomyolysis. He carried a pathogenic mutation, NPHS2 p.V260E, reported in nephropathy and a new variant p.R838Q in SCN11A, a gene involved in familial episodic pain syndrome. Results suggest that drug-to-drug interactions coupled with the stress of exercise, coinheritance of HbAS and NPHS2 p.V260E, and p. R838Q in SCN11A contributed to exertional rhabdomyolysis, recurrent hematuria with proteinuria, and episodic pain, respectively. This case underscores the importance of comprehensive clinical and genetic evaluations to identify underlying causes of health complications reported in SCT individuals. PubDate: Wed, 07 Nov 2018 06:42:30 +000
Abstract: We report a preterm female infant with intrauterine growth retardation, dysmorphic facies, missing rib, small hands and feet, and hemihypertrophy. The results of whole genome SNP microarray analysis showed approximately 77 Kb interstitial deletion of the short arm of chromosome 11 (11p15.4). We report novel clinical findings of this rare genetic condition. PubDate: Tue, 30 Oct 2018 00:00:00 +000
Abstract: Rothmund-Thomson syndrome is a genetic disorder with characteristic findings in childhood as well as a predisposition to osteosarcoma, skin cancer, and hematological malignancy. We present the first reported case of duodenal malignancy in a patient with Rothmund-Thompson syndrome. An enlarged Virchow’s node was noted and an advanced duodenal adenocarcinoma was diagnosed shortly thereafter. The features of Rothmund-Thomson syndrome are discussed, as well as current management and screening guidelines for duodenal adenocarcinoma. PubDate: Thu, 25 Oct 2018 00:00:00 +000
Abstract: The autosomal recessive cerebellar ataxias (ARCA) affect both the central and the peripheral nervous systems. They are also characterized by a relatively high level of genetic heterogeneity with well over 40 genes already implicated. The present study aimed to identify the gene mutation responsible for a complex phenotype comprising cerebellar ataxia and intellectual disability segregating in an Omani consanguineous family. Homozygosity-guided exome data analysis identified a novel frameshift mutation (c.2319_2322del) within the sorting nexin 14 gene (SNX14), which predicts complete absence of the SNX14 encoded protein. Segregation within the family of the sequence variation is consistent with its pathogenic role. Importantly, loss-of-function mutations in SNX14 have recently been described as a cause of a clinically distinguishable recessive syndrome consisting of cerebellar atrophy, ataxia, coarsened facial features, and intellectual disability. This study expands the genetic diversity of ataxia genes in the Omani population and have important implications for the clinical and molecular diagnosis of this condition in affected individuals. PubDate: Wed, 24 Oct 2018 00:00:00 +000
Abstract: Hajdu-Cheney Syndrome (HSC) is a rare multisystem disease in which the phenotype involves acro-osteolysis, severe osteoporosis, short stature, wormian bones, facial dysmorphism, central neurological abnormalities, cardiovascular defects, and polycystic kidneys. We describe an infant with severe manifestations of HCS in whom congenital glaucoma was a significant early feature, which has not been reported to date. HCS cases reported to date have involved truncating mutations in exon 34 of NOTCH2 upstream the PEST domain that lead to the development of a truncated and stable NOTCH2 protein which upregluates notch signaling. We describe a hitherto undescribed missense mutation that is predicted to be pathogenic, with functional characterization remaining to be performed. Serpentine fibula-polycystic kidney syndrome (SFPKS) is allelic to HCS and commonly associated with missense NOTCH2 mutations. Our patient provides new ophthalmological manifestations of HCS and provides insight into the potential role of notch signaling in the anterior chamber development. PubDate: Sun, 21 Oct 2018 00:00:00 +000
Abstract: Hereditary sensory and autonomic neuropathy type I (HSAN I) is an autosomal dominant disease characterized by distal sensory loss, pain insensitivity, and autonomic disturbances. The major underlying causes of HSAN I are point mutations in the SPTLC1 gene. Patients with mutations in the SPTLC1 genes typically exhibit dense sensory loss and incidence of lancinating pain. Although most of these mutations produce sensory loss, it is unclear which mutations would lead to the painful phenotype. In this case series, we report that the V144D mutation in SPTLC1 gene may relate to both painful and painless peripheral neuropathies. The unique clinical phenotype of this mutation may guide clinical workup and treatment for patients with painful and painless neuropathies. PubDate: Thu, 18 Oct 2018 00:00:00 +000
Abstract: Activating mutations in thyrotropin receptor (TSHR) have been previously described in the context of nonautoimmune hyperthyroidism and thyroid adenomas. We describe, for the first time, a mutation in TSHR contributing to follicular thyroid carcinoma (FTC) in an adolescent. A 12-year-old girl presented with a right-sided neck swelling, increasing in size over the previous four weeks. Clinical examination revealed a firm, nontender thyroid nodule. Ultrasound scan of the thyroid showed a heterogeneous highly vascular mass. Thyroid function tests showed suppressed TSH [C, p.Ile568Thr) in TSHR. Papillary thyroid carcinomas constitute the most common thyroid malignancy in childhood, while FTC is rare. FTC due to TSHR mutation suggests an underlying, yet to be explored, molecular pathway leading to the development of malignancy. The case is also unique in that the clinical presentation of FTC as a toxic thyroid nodule has not been previously reported in children. PubDate: Wed, 17 Oct 2018 06:31:24 +000
Abstract: CACNA2D2 encodes an auxiliary subunit of the voltage-dependent calcium channel. To date, there have only been two reports of individuals with early-infantile epileptic encephalopathy due to CACNA2D2 mutations. In both reports, patients were homozygous for the identified variants. Here, we report a patient with epileptic encephalopathy and cerebellar atrophy who was found to have two novel variants in the CACNA2D2 gene: c.782C>T (p.Pro261Leu) and c.3137T>C (p.Leu1046Pro), by whole-exome sequencing. The variants were shown to be inherited in trans and the unaffected parents were confirmed to be heterozygous carriers. This is the third report of recessive CACNA2D2 variants associated with disease and the first report of compound heterozygous variants. The clinical description of this new case highlights the phenotypic similarities amongst individuals with CACNA2D2-related disease and suggests that CACNA2D2 should be considered as a differential diagnosis in individuals with cerebellar dysfunction and multiple seizure types that begin in the first year of life. PubDate: Mon, 15 Oct 2018 06:43:02 +000
Abstract: This case series of three children reports clinical features and chromosomal abnormalities seen in a craniofacial clinic. All presented with orofacial cleft, developmental or intellectual disability, and dysmorphism. Emanuel syndrome or supernumerary der (22)t(11; 22), the prototype of complex small supernumerary marker disorders, was seen in one child. Duplication 4q27q35.2 with concomitant deletion 21q22.2q22.3 and duplication 12p13.33p13.32 with concomitant deletion 18q22.3q23 seen in the remaining two children are not reported in literature. Maternal balanced translocation was established in both of these children. PubDate: Sun, 09 Sep 2018 06:50:59 +000
Abstract: Jumping translocations of 1q refer to the break-off of chromosome 1q as a donor fusing to two or more recipient chromosomes. We detected jumping translocations of 1q in three patients with initial diagnosis of myelodysplastic syndrome (MDS) and later progression to acute myeloid leukemia (AML). Review of literature found jumping translocations of 1q in 30 reported cases of MDS and AML. The cytogenetic findings from these 33 cases showed that seven cases had a stemline clone and 26 cases had de novo jumping translocations of 1q in which 5% of cell lineages had additional structural rearrangements. In 75% of cases, the 1q donor jumped to the short arm of recipient acrocentric chromosomes. Approximately 82% of the fusions occurred in the telomeric regions of short and long arms and 18% occurred in the pericentric or interstitial regions of recipient chromosomes. Hypomethylation of the donor 1q pericentromeric region and shortened telomeres in recipient chromosomes were associated with the formation of jumping translocations. Jumping translocations of 1q as an indication of chromosomal instability pose high risk for progression of MDS to AML and a poor prognosis. Further understanding of underlying genomic defects and their clinical significance will improve overall treatment and patient care. PubDate: Sun, 09 Sep 2018 06:44:14 +000
Abstract: Congenital myopathies are a group of rare inherited diseases, defined by hypotonia and muscle weakness. We report clinical and genetic characteristics of a male preterm newborn, whose phenotype was characterized by severe hypotonia and hyporeactivity, serious respiratory distress syndrome that required mechanical ventilation, clubfoot, and other dysmorphic features. The diagnostic procedure was completed with the complete exome sequencing of the proband and of his parents and his sister, which showed new mutations in the ryanodine receptor gene (RYR1), which maps to chromosome 19q13.2 and encodes the skeletal muscle isoform of a calcium-release channel in the sarcoplasmic reticulum (RyR1). This report confirms that early diagnosis and accurate study of genomic disorders are very important, enabling proper genetic counselling of the reproductive risk, as well as disease prognosis and patient management. PubDate: Wed, 01 Aug 2018 08:39:02 +000
Abstract: Constitutional (Biallelic) Mismatch Repair Deficiency is a rare autosomal recessive disorder characterized by numerous cancers presenting as early as the first decade of life. Biallelic germline variants in one of four mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) cause this devastating disease. Given the rarity of the syndrome, often-asymptomatic tumors, and overlap with neurofibromatosis-1, diagnosis is frequently unrecognized or delayed. We present a unique case of a 14-year-old female with minimal gastrointestinal symptoms diagnosed with invasive adenocarcinoma secondary to biallelic PMS2 variants. PubDate: Wed, 25 Jul 2018 06:58:16 +000
Abstract: Congenital muscle dystrophies (CMD) are genetically and clinically heterogeneous hereditary myopathies mainly with autosomal recessive type of inheritance. The most common form worldwide is considered to be merosin-deficient muscle dystrophy type 1A, called MDC1A (due to laminin-α2 defects as a result of LAMA2 gene mutation), accounting for 30-40% of total cases of CMD. The exact molecular and clinical diagnoses, respectively, are a prerequisite for the most effective treatment; sometimes orphan drugs exist for some rare diseases. One of such drugs is Tarix, which was FDA approved and announced in 2016 for treatment of MDC1A. Here we present a patient diagnosed postmortem as having early-onset LAMA2-related muscular dystrophy as a result of mutations in LAMA2, identified by Sanger sequencing in his parents: a novel nonsense mutation c.4452T>A in exon 31, identified in the mother, and a known pathogenic nonsense mutation c.2901C>A in exon 21, detected in the father. The truncating nature of both nonsense mutations made the clinical presentation severe and the outcome fatal. Genetic analysis in such cases of muscle dystrophy is of utmost impact, because it makes the correct diagnosis with at least some specific options for treatment, makes the prognosis depending on the severity of mutation discovered, determines reproductive risk, and offers prophylaxis in the family by means of prenatal or preimplantation diagnostics. PubDate: Wed, 25 Jul 2018 00:00:00 +000
Abstract: Limb girdle muscular dystrophies (LGMDs) are a heterogeneous group of genetic myopathies leading primarily to proximal muscle weakness. It is caused by mutations at over 50 known genetic loci typically from mutations in genes encoding constituents of the sarcolemmal dystrophin complex or related functions. Herein we describe the case of two siblings with LGMD that were investigated using whole-exome sequencing followed by Sanger sequencing validation of a specific double-mutation in the TRAPPC11 gene. Further, from parental sequencing we determined the mode of transmission, a double heterozygous mutation at the maternal and paternal alleles. The two mutations detected have not been described in other patients. PubDate: Mon, 16 Jul 2018 06:51:43 +000
Abstract: Alagille syndrome (MIM 118450) is an autosomal dominant disorder characterized by paucity of intrahepatic bile ducts, chronic cholestasis, pulmonary stenosis, butterfly-like vertebrae, posterior embryotoxon, and dysmorphic facial features. Most cases are caused by JAG1 gene mutations. We report the case of a 2-year-old Mexican mestizo patient with Alagille syndrome, having exhibited jaundice and cholestatic syndrome as of three weeks of age. Sequencing analysis of the JAG1 gene revealed the novel heterozygous mutation c.91dupG that originates a truncated protein and therefore a possibly diminished activation of the Notch signaling pathway. The latter may explain the severe phenotype of the patient. Since the mutation was not identified in the parents, it was considered a de novo event, highlighting the importance of molecular diagnosis and genetic counseling. In conclusion, this report widens the spectrum of JAG1 gene mutations associated with Alagille syndrome. PubDate: Mon, 25 Jun 2018 00:00:00 +000
Abstract: Microdeletions at 19p13.3 are rarely reported in the medical literature with significant phenotypic variability. Among the reported cases, common clinical manifestations have included developmental delay, facial dysmorphism, and hypotonia. Herein we described a child with a de novo 19p13.3 microdeletion, proximal to the reported cases of 19p13.3 microdeletion/duplication, with ocular manifestations of bilateral ocular colobomata complicated with microphthalmos and cataract, associated with short stature. This case highlights the phenotypic heterogeneity of deletions in the 19p13.3 region. PubDate: Mon, 30 Apr 2018 07:38:08 +000
Abstract: We present a 43-year-old man with aortic root dilation, mitral valve prolapse, and marfanoid appearance, who presented with acute onset left leg pain. He underwent a Doppler ultrasound that revealed left popliteal artery aneurysm with thrombus. CT angiogram showed bilateral popliteal artery aneurysms. After repairing of his left popliteal artery aneurysm, he was sent for genetic evaluation. He was diagnosed with Marfan syndrome (MFS) based on the revised Ghent criteria and then underwent FBN1 sequencing and deletion/duplication analysis, which detected a novel pathogenic variant in gene FBN1, denoted by c.5872 T>A (p.Cys1958Ser). MFS is a connective tissue disorder with an autosomal dominant inheritance due to pathogenic variants in FBN1 that encodes Fibrillin-1, a major element of the extracellular matrix, and connective tissue throughout the body. MFS involves multiple systems, most commonly the cardiovascular, musculoskeletal, and visual systems. In our case we present a rare finding of bilateral popliteal artery aneurysms in a male patient with MFS. PubDate: Thu, 29 Mar 2018 00:00:00 +000
Abstract: Chronic urticaria is a common condition characterized by recurrent hives lasting several weeks or months and is usually idiopathic. Approximately half of the individuals with chronic urticaria will present with episodes of angioedema that can be severe and debilitating. In this report, we describe a 47-year-old Hispanic male who presented initially for an evaluation of chronic hives following hospitalization due to hive-induced anaphylaxis. The individual had a history significant for urticaria and angioedema beginning in his early 30s. Interestingly, both the individual’s 41-year-old sister and 12-year-old daughter were also affected with chronic urticaria and severe angioedema. Whole exome sequencing of the proband and several family members revealed a heterozygous variant of uncertain significance in exon 2 of TNFAIP3, denoted as c.65G>A (p.R22Q), in all affected members. Variants in TNFAIP3 have been associated with multiple autoimmune diseases, susceptibility to allergy and asthma, and periodic fever syndromes, suggesting that this variant could potentially play a role in disease. PubDate: Thu, 22 Feb 2018 00:00:00 +000
Abstract: The occurrence of simultaneous de novo chromosomal aberrations is extremely rare. Here, we describe two, previously unreported, simultaneous de novo interstitial duplications of chromosomes 7p and 15q. Amniocentesis was completed for a healthy gravida 4 para 3 woman due to her advanced maternal age and concurrent ultrasound findings of partial vermian agenesis, choroid-plexus cysts, and hypoplastic nasal bone. Cytogenetic analysis of cultured amniocytes by conventional chromosome analysis, comparative genomic hybridization, and fluorescence in situ hybridization revealed two interstitial duplications of the chromosomal regions 7p22.1p21.1 and 15q24.1, leading to partial trisomy of 7p and 15q and karyotype 46,XY,dup(7)(p22.1-p21.1),dup (15)(q24.1). Parental chromosomal analysis did not identify any heritable changes, suggesting both mutations were de novo in nature. Postnatal examination of the neonate was significant for low set ears, thick helices, flat nasal bridge, ankyloglossia, and aberrant head shape and size concerning for craniosynostosis. Postnatal MRI was consistent with Dandy-Walker variant showing hypogenesis of the inferior cerebellar vermis. To our knowledge, there are no prenatal or postnatal reports of comparable duplications involving these two regions simultaneously. Continued observation of the neonate may reveal further phenotypic consequences of these two simultaneous de novo interstitial duplications. PubDate: Sun, 11 Feb 2018 00:00:00 +000
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