4 research outputs found
Investigation of Genetic Causes in Oculoauriculovertebral Spectrum Etiology
Oculo-Auriculo-Vertebral Spectrum (OAVS) is a
genetically and phenotypically heterogeneous disorder which occurs due to a
developmental defect in the first and second pharyngeal arches. In this study, 23
OAVS patients with diverse clinical findings were studied to identify the genetic
etiology of this disorder. Patients were screened for copy number variations using the
Affymetrix CytoScan Optima array Kit and also screened for MYT1 mutations using
BigDye terminator on an ABI Prism 3500 genetic analyzer. Furthermore, two
patients underwent WES analysis. Using these approaches, three CNVs (one
deletion, two duplications) were found in chromosomes 8, 15, 16. The clinical
relevance of the copy number variations is discussed within the framework of
incomplete penetrance and monoallelic expression. In addition, the deletion on the
8th chromosome was thought to be associated with clinical findings by altering the
genome architecture. In addition, a de novo unbalanced translocation; between X and
4th chromosomes was found in one of the patients and was considered pathogenic.
No causative mutation was found in MYT1 gene. WES analysis revealed a novel
heterozygous nonsense mutation in EFTUD2; responsible for Mandibulofacial
Dysostosis with Microcephaly that has common clinical findings with OAVS. In the
other patient who underwent WES analysis a novel heterozygous missense mutation
was identified in RNF213, which was previously suspected as a candidate gene for
OAVS. Duplication of 16p13.11 region, aneuploidies of X chromosome and
EFTUD2 mutations were previously implicated in OAVS molecular etiology. This
study provides further genetic heterogeneity to this disorder, confirming the
importance of microarray-based studies and whole exome sequencing analysis in
patients with a complex phenotypic disorder such as OAVS.Bu çalışma HÜTF Bilimsel Araştırma Projeleri
Koordinasyon Birimi tarafından desteklenmiştir (TTU-2018-16935).Okulo-aurikulo-vertebral spektrum
(OAVS) birinci ve ikinci farengeal arkların gelişimsel defektleri sonucunda oluşan
genetik ve fenotipik heterojenite gösteren nadir bir hastalıktır. Bu çalışmada çeşitli
klinik bulgulara sahip 23 OAVS hastasında genetik etyoloji araştırılmıştır. İlk
basamakta kopya sayısı değişikliklerini saptamaya yönelik Affymetrix
CytoScan Optima platformunda mikrodizin analizleri yapılmıştır. Sonra ABI Prism
3500 cihazında Sanger dizileme yöntemi ile MYT1 geni dizi analizleri
tamamlanmıştır. Ek olarak; iki hastada tüm ekzom dizileme gerçekleştirilmiştir. Bu
yaklaşımlar sonucunda; üç hastada 8., 15., ve 16. kromozomlarda kopya sayısı
değişiklikleri gösterilmiştir. İlgili değişikliklerin klinik ilişkisi inkomplet penetrans
ve monoalelik ekspresyon çerçevesinde tartışılmıştır. Ayrıca 8. kromozomdaki
delesyonun genom mimarisini değiştirerek klinik ile ilişkili olacağı düşünülmüştür.
Ek olarak; hastaların bir tanesinde periferik kandan yapılan kromozom analizi
sonucunda X ve 4. kromozomlar arasında de novo dengesiz translokasyon
gösterilmiş ve patojenik olarak değerlendirilmiştir. MYT1 geni dizi analizi sonucunda
klinik anlamlı bir değişiklik bulunmamıştır. Tüm ekzom dizileme analizi sonucunda
ise; hastaların birinde OAVS ile örtüşen klinik bulgular görülen Mandibulofasiyal
Dizostozis ve Mikrosefali birlikteliğinden sorumlu EFTUD2 geninde novel
heterozigot mutasyon saptanmıştır. Tüm ekzom dizileme yapılan diğer hastada;
OAVS aday geni olarak nitelendirilen RNF213 geninde novel missense bir mutasyon
gözlenmiştir. 16p13.11 bölgesi duplikasyonu, X kromozomu anöploidileri ve
EFTUD2 genindeki değişiklikler önceki çalışmalarda da OAVS moleküler
etyolojisinde tanımlanmış durumdadır. Hastalarda farklı kromozomlarda kopya
sayısı değişikliklerinin yanı sıra tek gen değişikliklerinin gösterilmesi spektrumdaki
geniş genetik heterojeniteyi desteklemektedir. Bu çalışma; OAVS benzeri kompleks
fenotipik bulgulara sahip hastalıklarda genetik etyolojinin tanımlanmasında
mikrodizin analizi ve tüm ekzom dizileme gibi genom boyu ölçeğinde
gerçekleştirilen yöntemlerin önemini ortaya koymaktadır
Clinical Management in Systemic Type Pseudohypoaldosteronism Due to <i>SCNN1B</i> Variant and Literature Review
A Monogenic Disease with a Variety of Phenotypes: Deficiency of Adenosine Deaminase 2
Objective: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder associated with ADA2 mutations. We aimed to investigate the characteristics and ADA2 enzyme activities of patients with DADA2 compared to non-DADA2 patients.
Methods: This is a descriptive study of 24 patients with DADA2 who were admitted to the Adult and Pediatric Rheumatology, Pediatric Haematology, and Pediatric Immunology Departments of Hacettepe University. All ADA2 exons were screened by Sanger sequencing. Serum ADA2 enzyme activity was measured by modified spectrophotometric method.
Results: Twenty-four patients with DADA2 were included: 14 with polyarteritis nodosa (PAN)-like phenotype (Group 1); 9 with Diamond-Blackfan anemia (DBA)-like features, and 1 with immunodeficiency (Group 2). Fourteen PAN-like DADA2 patients did not have the typical thrombocytosis seen in classic PAN. Inflammatory attacks were evident only in Group 1 patients. Serum ADA2 activity was low in all patients with DADA2 except one, who was tested after hematopoietic stem cell transplantation. There was no significant difference in ADA2 activities between PAN-like and DBA-like patients. In DADA2 patients with one ADA2 mutation, serum ADA2 activities were as low as those of patients with homozygote DADA2. ADA2 activities were normal in non-DADA2 patients. ADA2 mutations were affecting the dimerization domain in Group 1 patients and the catalytic domain in Group 2 patients.
Conclusion: We suggest assessing ADA2 activity along with genetic analysis because there are patients with one ADA2 mutation and absent enzyme activity. Our data suggest a possible genotype-phenotype correlation in which dimerization domain mutations are associated with PAN-like phenotype, and catalytic domain mutations are associated with hematological manifestations.PubMe