scholarly journals First-Tier Array CGH in Clinically Variable Entity Diagnosis: 22q13.3 Deletion Syndrome

2020 ◽  
Author(s):  
Magdalena Budisteanu ◽  
Andreea Tutulan-Cunita ◽  
Ina Ofelia Focsa ◽  
Sorina Mihaela Papuc ◽  
Aurora Arghir
Keyword(s):  
Copy Number ◽  
Genetic Disorder ◽  
Mutation Screening ◽  
Pathogenic Mutation ◽  
Deletion Syndrome ◽  
Chromosomal Microarray ◽  
Loss Of Function ◽  
Clear Cut ◽  
Diagnostic Approaches ◽  
Next Generation Sequencing Ngs

Phelan-McDermid (PMS) or 22q13 deletion syndrome (OMIM 606232) is a rare genetic disorder with highly variable clinical presentation. The phenotype includes generalized neonatal hypotonia, developmental delay with intellectual disability and delayed speech, mild dysmorphic features, and autistic behavior. The genetic defects of PMS consist of 22q13.3 deletions or chromosomal structural rearrangements involving SHANK3 gene; the loss of function mutations of SHANK3 gene was reported in a minority of cases. The 22q13.3 deletions vary in size, from 0.2 to over 9 Mb, and, although larger deletions are generally associated with more severe phenotypes, the genotype-phenotype correlations are not clear-cut for all patients. SHANK3 is considered the main candidate gene for the neurologic features of PMS. PMS is a rare disorder, often underdiagnosed. There are no established clinical diagnostic criteria for PMS. The genetic tests typically used are chromosomal microarray and multiplex ligation-dependent probe amplification (MLPA) or fluorescent in situ hybridization (FISH) for copy number analysis of SHANK3 gene; next-generation sequencing (NGS) or Sanger sequencing is used for pathogenic mutation screening of SHANK3. In this chapter, we report three cases with PMS and summarize the clinical and genetic diagnostic approaches of this condition, highlighting the role of chromosomal microarray technology in the identification of rare, but significantly impacting patient’s life, DNA copy number abnormalities.

scholarly journals Peruvian Newborn Male with 3p13 Deletion Syndrome Encompassing the FOXP1 Gene: Review of the Literature

2020 ◽  
Vol 09 (04) ◽  
pp. 270-278
Author(s):  
Hugo H. Abarca-Barriga ◽  
Milana Trubnykova ◽  
Félix Chavesta-Velásquez ◽  
Claudia Barletta-Carrillo ◽  
Marco Ordoñez-Linares ◽  
...  
Keyword(s):  
Copy Number ◽  
Choanal Atresia ◽  
Copy Number Variant ◽  
Autism Spectrum ◽  
Deletion Syndrome ◽  
Chromosomal Microarray ◽  
Facial Dysmorphism ◽  
Chromosomal Microarray Analysis ◽  
Heart Malformation ◽  
Number Variation

AbstractCopy number variation in loss of 3p13 is an infrequently reported entity characterized by hypertelorism, aniridia, microphthalmia, high palate, neurosensorial deafness, camptodactyly, heart malformation, development delay, autism spectrum disorder, seizures, and choanal atresia. The entity is caused probably by haploinsufficiency for FOXP1, UBA3, FAM19A1, and MITF. We report a newborn male with hypotonia, facial dysmorphism, heart malformation, and without clinical diagnosis; nevertheless, the use of appropriate genetic test, such us the chromosomal microarray analysis allowed identification of a copy number variant in loss of 5.5 Mb at chromosome 3 (p13-p14.1), that included 54 genes, encompassing FOXP1 gene. We compare the findings in our Peruvian patient to those of earlier reported patients; furthermore, add new signs for this entity.

scholarly journals Favorable response to carbamazepine therapy in genetically proven myoclonus-dystonia child

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Mohammed F. Aljabri ◽  
Naglaa M. Kamal ◽  
Abdulrhman Alghamdi ◽  
Hamdan Alghamdi ◽  
Naif Alomairi
Keyword(s):  
Genetic Disorder ◽  
Pathogenic Mutation ◽  
The Other ◽  
Loss Of Function ◽  
Case Presentation ◽  
Carbamazepine Therapy ◽  
Myoclonus Dystonia ◽  
Back Ward

Abstract Background Myoclonus dystonia (MDS) is a dominantly inherited genetic disorder caused by loss-of-function mutations in the epsilon sarcoglycan gene (SGCE). Case presentation We here in report a twenty months old Saudi boy who presented to us with a concern that the child is unable to walk properly. On assessment, he was flexing his left arm and left leg that usually followed by a back-ward fall. Diagnosis of dystonia induced with initiation of movement was suggested that later on proven genetically to be pathogenic mutation of sarcoglycan gene. Carbamazepine therapy was initiated with dramatic response. Response was maintained at 4 years follow up. Conclusions Our patient and the other previously reported cases might highlight the response of SGCE mutations to carbamazepine therapy.

scholarly journals Heterozygous Deletions in MKRN3 Cause Central Precocious Puberty Without Prader-Willi Syndrome

2020 ◽  
Vol 105 (8) ◽  
pp. 2732-2739
Author(s):  
Brooke N Meader ◽  
Alessandro Albano ◽  
Hilal Sekizkardes ◽  
Angela Delaney
Keyword(s):  
Precocious Puberty ◽  
Copy Number ◽  
Genetic Diagnosis ◽  
Central Precocious Puberty ◽  
Chromosomal Microarray ◽  
Imprinted Genes ◽  
Prader Willi Syndrome ◽  
Loss Of Function ◽  
Gene Deletions ◽  
Pubertal Onset

Abstract Context Loss-of-function mutations in the imprinted genes MKRN3 and DLK1 cause central precocious puberty (CPP) but whole gene deletions have not been reported. Larger deletions of the chromosome 15q11-13 imprinted locus, including MKRN3, cause Prader-Willi syndrome (PWS). CPP has been reported in PWS but is not common, and the role of MKRN3 in PWS has not been fully elucidated. Objective To identify copy number variants in puberty-related, imprinted genes to determine their role in CPP. Methods Probands with idiopathic CPP had chromosomal microarray (CMA) and targeted deletion/duplication testing for MKRN3 and DLK1. Results Sixteen female probands without MKRN3 or DLK1 variants identified by Sanger sequencing were studied. Whole gene deletions of MKRN3 were identified in 2 subjects (13%): a complete deletion of MKRN3 in Patient A (pubertal onset at 7 years) and a larger deletion involving MAGEL2, MKRN3, and NDN in Patient B (pubertal onset 5.5 years). Both were paternally inherited. Patient B had no typical features of PWS, other than obesity, which was also present in her unaffected family. Conclusions We identified 2 cases of whole gene deletions of MKRN3 causing isolated CPP without PWS. This is the first report of complete deletions of MKRN3 in patients with CPP, emphasizing the importance of including copy number variant analysis for MKRN3 mutation testing when a genetic diagnosis is suspected. We speculate that there is a critical region of the PWS locus beyond MKRN3, MAGEL2, and NDN that is responsible for the PWS phenotype.

Osteogenesis Imperfecta and Split Foot Malformation due to 7q21.2q21.3 Deletion Including COL1A2, DLX5/6 Genes: Review of the Literature

2021 ◽  
Author(s):  
Özden Öztürk ◽  
Haydar Bagis ◽  
Semih Bolu
Keyword(s):  
Osteogenesis Imperfecta ◽  
Copy Number ◽  
Bone Fractures ◽  
Genetic Disorder ◽  
Rare Condition ◽  
Copy Number Variant ◽  
Joint Laxity ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Number Variation

AbstractCopy number variation in loss of 7q21 is a genetic disorder characterized by split hand/foot malformation, hearing loss, developmental delay, myoclonus, dystonia, joint laxity, and psychiatric disorders. Osteogenesis imperfecta caused by whole gene deletions of COL1A2 is a very rare condition. We report a Turkish girl with ectrodactyly, joint laxity, multiple bone fractures, blue sclera, early teeth decay, mild learning disability, and depression. A copy number variant in loss of 4.8 Mb at chromosome 7 (q21.2q21.3) included the 58 genes including DLX5, DLX6, DYNC1I1, SLC25A13, SGCE, and COL1A2. They were identified by chromosomal microarray analysis. We compared the findings in our patients with those previously reported. This case report highlights the importance of using microarray to identify the genetic etiology in patients with ectrodactyly and osteogenesis imperfecta.

Multiple Congenital Anomalies and Global Developmental Delay in a Patient with Interstitial 6q25.2q26 Deletion: A Diagnostic Odyssey

2018 ◽  
Vol 156 (4) ◽  
pp. 191-196
Author(s):  
Prabakaran Paulraj ◽  
Janice C. Palumbos ◽  
Amanda Openshaw ◽  
John C. Carey ◽  
Reha M. Toydemir
Keyword(s):  
Congenital Anomalies ◽  
Chromosomal Abnormalities ◽  
Genetic Disorder ◽  
Deletion Syndrome ◽  
Growth Delay ◽  
Global Developmental Delay ◽  
Loss Of Function ◽  
Multiple Congenital Anomalies ◽  
Microdeletion Syndromes ◽  
Cornelia De Lange

Interstitial deletions involving 6q25 are rare chromosomal abnormalities associated with distinctive phenotypic features. We describe a 9-year-old boy who was followed from his infancy due to his multiple congenital anomalies and complex medical history. Over the years, a number of diagnoses were considered including Cornelia de Lange syndrome, Rubinstein-Taybi syndrome, as well as “a novel genetic disorder.” Various genetic tests, including a BAC-based array-CGH analysis, were reported as normal. Recently, a SNP-based microarray analysis was performed and showed an 11.1-Mb deletion from 6q25.2 to 6q26, including ARID1B and ZDHHC14. Recent literature suggests that the 6q25 deletion syndrome is a recognizable entity characterized by growth delay, developmental disabilities, microcephaly, hearing loss, and variable other malformations including cleft palate. These features overlap with those of Coffin-Siris syndrome, which is caused by deletions and loss-of-function mutations of ARID1B. Retrospectively, this patient has features resembling both Coffin-Siris and 6q25 microdeletion syndromes.

scholarly journals Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

2021 ◽  
Vol 22 (7) ◽  
pp. 3786
Author(s):  
Andreas Brodehl ◽  
Alexey Meshkov ◽  
Roman Myasnikov ◽  
Anna Kiseleva ◽  
Olga Kulikova ◽  
...  
Keyword(s):  
Medical History ◽  
Splice Site Mutation ◽  
Pathogenic Mutation ◽  
Large Deletion ◽  
Loss Of Function ◽  
Arrhythmogenic Cardiomyopathy ◽  
Site Mutation ◽  
Snp Arrays ◽  
Number Of Patients ◽  
History Of

About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.

scholarly journals Inborn errors of immunity—recent advances in research on the pathogenesis

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Motoi Yamashita ◽  
Kento Inoue ◽  
Tsubasa Okano ◽  
Tomohiro Morio
Keyword(s):  
Immune System ◽  
Hematopoietic Cell Transplantation ◽  
Epigenetic Modification ◽  
Genetic Disorder ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Whole Genome Analysis ◽  
Curative Therapy ◽  
Inborn Errors Of Immunity ◽  
Recent Advances

AbstractPrimary immunodeficiency (PID) is a genetic disorder with a defect of one of the important components of our immune system. Classical PID has been recognized as a disorder with loss of function of the immune system. Recent studies have unveiled disorders with immune dysfunction with autoimmunity, autoinflammation, allergy, or predisposition to malignancy. Some of them were caused by an augmented immune function or a defect in immune regulation. With this background, the term inborn errors of immunity (IEI) is now used to refer to PID in the International Union of Immunological Societies (IUIS) classification. More than 400 responsible genes have been identified in patients with IEI so far, and importantly, many of them identified lately were caused by a heterologous mutation. Moreover, the onset is not necessarily in childhood, and we started seeing more and more IEI patients diagnosed in adulthood in the clinical settings. Recent advances in genetic analysis, including whole-exome analysis, whole-genome analysis, and RNA-seq have contributed to the identification of the disease-causing gene mutation. We also started to find heterogeneity of phenotype even in the patients with the same mutation in the same family, leading us to wonder if modifier gene or epigenetic modification is involved in the pathogenesis. In contrast, we accumulated many cases suggesting genetic heterogeneity is associated with phenotypic homogeneity. It has thus become difficult to deduce a responsible gene only from the phenotype in a certain type of IEI. Current curative therapy for IEI includes hematopoietic cell transplantation and gene therapy. Other curative therapeutic modalities have been long waited and are to be introduced in the future. These include a small molecule that inhibits the gain-of-function of the molecule- and genome-editing technology. Research on IEI will surely lead to a better understanding of other immune-related disorders including rheumatic diseases and atopic disorders.

scholarly journals Case of Small Vessel Disease Associated with COL4A1 Mutations following Trauma

2015 ◽  
Vol 7 (2) ◽  
pp. 142-147 ◽  
Author(s):  
Joao McONeil Plancher ◽  
Robert B. Hufnagel ◽  
Achala Vagal ◽  
Katrina Peariso ◽  
Howard M. Saal ◽  
...  
Keyword(s):  
Contrast Enhancement ◽  
Head Trauma ◽  
Small Vessel Disease ◽  
Genetic Disorder ◽  
Single Gene ◽  
Young Patients ◽  
Pathogenic Mutation ◽  
Small Vessel ◽  
Vessel Disease ◽  
History Of

With this case report, we would like to heighten the awareness of clinicians about COL4A1 as a single-gene disorder causing cerebral small vessel disease and describe a previously unreported pathogenic missense substitution in COL4A1 (p.Gly990Val) and a new clinical presentation. We identified a heterozygous putatively pathogenic mutation of COL4A1 in a 50-year-old female with a history of congenital cataracts and glaucoma who presented with multiple diffusion-positive infarcts and areas of contrast enhancement following mild head trauma. We believe that this presentation of multiple areas of acute brain and vascular injury in the setting of mild head trauma is a new manifestation of this genetic disorder. Imaging findings of multiple acute infarcts and regions of contrast enhancement with associated asymptomatic old deep microhemorrhages and leukomalacia in adults after head trauma should raise a high suspicion for a COL4A1 genetic disorder. Radiographic patterns of significant leukoaraiosis and deep microhemorrhages can also be seen in patients with long-standing vasculopathy associated with hypertension, which our patient lacked. Our findings demonstrate the utility of genetic screening for COL4A1 mutations in young patients who have small vessel vasculopathy on brain imaging but who do not have significant cardiovascular risk factors.

scholarly journals Genotype-Phenotype correlation in Dravet Syndrome with SCN1A mutation increase efficiency of molecular diagnosis

2012 ◽  
Vol 18 (2) ◽  
pp. 60-62
Author(s):  
MC Gonsales ◽  
P Preto ◽  
MA Montenegro ◽  
MM Guerreiro ◽  
I Lopes-Cendes
Keyword(s):  
Protein Function ◽  
Copy Number ◽  
Mutation Screening ◽  
Copy Number Variants ◽  
Febrile Seizures ◽  
Copy Number Variations ◽  
Dravet Syndrome ◽  
Missense Mutations ◽  
The Impact ◽  
Doose Syndrome

OBJECTIVES: The purpose of this study was to advance the knowledge on the clinical use of SCN1A testing for severe epilepsies within the spectrum of generalized epilepsy with febrile seizures plus by performing genetic screening in patients with Dravet and Doose syndromes and establishing genotype-phenotype correlations. METHODS: Mutation screening in SCN1A was performed in 15 patients with Dravet syndrome and 13 with Doose syndrome. Eight prediction algorithms were used to analyze the impact of the mutations in putative protein function. Furthermore, all SCN1A mutations previously published were compiled and analyzed. In addition, Multiplex Ligation-Dependent Probe Amplification (MLPA) technique was used to detect possible copy number variations within SCN1A. RESULTS: Twelve mutations were identified in patients with Dravet syndrome, while patients with Doose syndrome showed no mutations. Our results show that the most common type of mutation found is missense, and that they are mostly located in the pore region and the N- and C-terminal of the protein. No copy number variants in SCN1A were identified in our cohort. CONCLUSIONS: SCN1A testing is clinically useful for patients with Dravet syndrome, but not for those with Doose syndrome, since both syndromes do not seem to share the same genetic basis. Our results indicate that indeed missense mutations can cause severe phenotypes depending on its location and the type of amino-acid substitution. Moreover, our strategy for predicting deleterious effect of mutations using multiple computation algorithms was efficient for most of the mutations identified.

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