Pathogenic homozygous mutation in the pleckstrin homology domain of RASA1 is responsible for familial tricuspid atresia in an Iranian consanguineous family

Objective: Tricuspid atresia [TA] is a rare life-threatening form of congenital heart defect [CHD]. The genetic mechanisms underlying TA are not clearly understood. According to previous studies, the endocardial cushioning event, as the primary sign of cardiac valvulogenesis, is governed by several overlapping signaling pathways including Ras/ ERK pathway. RASA1, a regulator of cardiovascular development, is involved in this pathway and its haploinsufficiency [due to heterozygous mutations] has been identified as the underlying etiology of the autosomal dominant capillary malformation/arteriovenous malformation [CM/AVM]

Materials and Methods: In this prospective study, we used whole exome sequencing [WES] followed by serial bioinformatics filtering steps for two siblings with TA and early onset CM. Their parents were consanguineous which had a history of recurrent abortions. Patients were carefully assessed to exclude extra-cardiac anomalies

Results: We identified a homozygous RASA1 germline mutation, c.1583A>G [p.Tyr528Cys] in the family. This mutation lies in the pleckstrin homology [PH] domain of the gene. The parents who were heterozygous for this variant displayed CM

Conclusion: This is the first study reporting an adverse phenotypic outcome of a RASA1 homozygous mutation. Here, we propose that the phenotypic consequence of the homozygous RASA1 p.Tyr528Cys mutation is more serious than the heterozygous type. This could be responsible for the TA pathogenesis in our patients. We strongly suggest that parents with CM/AVM should be investigated for RASA1 heterozygous mutations. Prenatal diagnosis and fetal echocardiography should also be carried out in the event of pregnancy in heterozygous parents

Fraccaro syndrome: report of two Iranian casesþ:þ an infant and an adult in a family

49,XXXXY is rare chromosomal pattern and these patients have mental retardation, small penis,cryptorchidism and skeletal anomalies. We reported a 10 month-old boy who has hypotonia, microcephaly, hypertelorism, depressed nasal bridge, epicanthic folds and bilateral multiple ear tags, high arched palate, down set ears, micrognathia and congenital heart disease such as patent ductus arteriosus [PDA], Atrial septaldefect [ASD], mild pulmonary stenosis. Among the skeletal anomalies, he has kyphoscoliosis, clinodactyly of the fourth and fifth fingers of both hands, and bilateral club foot and unilateral dysplasia of the hip. Karyotype was found as 49,XXXXY[44]/48,XXXY[6] and this cytogenetic analysis was help to establish clinical diagnosis Fraccaro syndrome

Mutational screening of ARX gene in Iranian families with X-linked intellectual disability

Mutations in the human aristaless-related homeobox [ARX] gene are amongst the major causes of developmental and neurological disorders. They are responsible for a wide spectrum of phenotypes, including nonsyndromic X-linked intellectual disability [NS-XLID], and syndromic [XLIDS] forms such as X-linked lissencephaly with abnormal genitalia [XLAG], Partington syndrome [PRTS], and X-linked infantile spasm syndrome [ISSX]. The recurrent 24 bp duplication mutation, c.428_451dup[24 bp], is the most frequent ARX mutation, which accounts for 40% of all cases reported to date. We have screened the entire coding sequences of the ARX gene in 65 Iranian families with intellectual disabilities in order to obtain the relative prevalence of ARX mutations. At first these families were screened for the most recurrent mutation, the c.428_451dup[24 bp]. For samples with negative results, single strand conformation polymorphism [SSCP] analysis was performed. We identified one family with the c.428_451dup[24 bp] duplication. Three shifts [one shift in exon 5 and two shifts in exon 4] were also identified among the total families. According to the results of the sequencing analysis, two shifts were not associated with any mutation and the other one was a c.1347C>T [p.G449G] substitution in exon 4. Hence, we suggest that molecular analysis of ARX mutations as a second cause of XLID should be considered as routine diagnostic procedure in any male who presents with either NS-XLID or XLIDS

[ maternally inherited balanced reciprocal translocation in a mentally retarded dysmorphic girl]

A 29 years old girl with various dimorphic features including short stature and webbed neck with mild to moderate mental retardation was referred to our center for chromosome investigation. Her parents were first cousins. The mother has had two previous miscarriages, one deceased son [12 years old] with apparently similar abnormal features to the proband with congenital heart problems, and one normal son [27 years old]. The patient, her mother and the brother, all were found to have an apparently balanced reciprocal translocation between the long arms of chromosomes 4 and 10. The breakpoint on chromosome 4 is at the distal end [4q35], while for chromosome 10, it is proximal to the centromere [10q11.2]. FISH studies using multiprobe subtelomeric specific probes as well as whole chromosome paints for chromosomes 4 and 10 were carried out in search of a genetic imbalance. The FISH results revealed no telomeric rearrangements and confirmed the balanced reciprocal translocation between chromosomes 4 and 10. To date, this is the first reported case of t[410][q35q11.2]

[Cockayne syndrome: reporting a case from Iran with a novel mutation]

Cockayne syndrome is a very rare genetic disorder with a recessive autosomal inheritance. The disease is characterized by dwarfism, microcephaly, mental retardation, deafness, photosensive dermatitis and a peculiar form of retinal pigmentation. We report here an Iranian family with one affected child who is suffering from Cockayne syndrome. Cardinal features were failure to thrive, short stature, premature aging, microcephaly, dysarthric speech, photosensivity, sunken eyes, and dental caries. There was no blindness or deafness, and the fundus examination showed tapetoretinal degeneration. Direct sequencing of all coding sequences of CSA and CSB genes, showed a novel mutation [c.2382+57G>T] in intron 10 of CSB that was not reported before. This variation might perturb splicing in CSB. However to prove the pathogenicity of this mutation mRNA analysis on fibroblast is planned to be investigated

[Prenatal diagnosis of chromosomal abnormalities by amniocentesis: report of 261 cases]

Amniocentesis is a technique for detection of chromosomal abnormalities in the unborn fetuses. The technique is being applied to the all high risk pregnancies, mostly in advanced maternal ages and abnormal results in the 1st or 2nd trimester pregnancies. In current situation, first trimester screening is being done in the 11 to 13 weeks and 6 days of gestation, and mid-trimester screening [between weeks 15 to 20]. We report the result of our samples in this article. 261 pregnancies were followed and screened by 1st and 2nd trimester screening by Iranian Fetal Foundation protocols in an 18 months period [from January 2007 to July 2008]. Advanced maternal ages [35 years and more], or detected a balanced structural chromosomal abnormalities in one of the parents were indications for amniocentesis in this group. Amniocentesis was performed in the 261 cases during the mentioned period. In all of the culture tubes [100%] cell growth was successful. Mean of the time for screening and reporting the results was 12 days. Twelve affected fetuses [4.6%] were detected. The most common abnormalities were Down's syndrome and balanced translocation. First and second trimester screening is recommended to all pregnancies by international FMF protocol. Whenever the results showed that the pregnancy is prone to the risk then amniocentesis is highly recommended to detect chromosomal abnormalities

[ syndrome resemble to CODAS: the first reported Iranian girl]

CODAS is a syndrome consisting of cerebral, ocular, dental, auricular, and skeletal abnormalities. Patients with this syndrome have psychomotor delay, mental retardation, generalized hypotonia, cataract, ptosis, abnormally shaped teeth, malformed ears, deafness, grooved nasal tip, radiological findings of spondylo-epiphyseal dysplasia, with delayed skeletal maturation and coronal vertebral clefts and short stature. We report on an Iranian girl with features resembling CODAS syndrome. She presented with facial dysmorphism, cataract, abnormally shaped teeth, malformed ear, radiological findings of metaphysio-epiphyseal dysplasia and growth and developmental delay. The underlying defect responsible for CODAS syndrome remains unknown. Many of the features suggest a possible underlying collagen gene defect. The fact that this child is the product of consanguineous marriage suggests the possibility of autosomal recessive inheritance

Chromosomal abnormalities in leukemia in Iran: a pilot study

Objective-To carry out cytogenetics investigations on bone marrow and peripheral blood samples obtained from patients with leukemia. Methods-A total of 35 bone marrow or blood samples from all types of leukemia patients was referred to the Cytogenetic Laboratory of Tehran University of Medical Sciences. The referral centers were the Hematology and Oncology Centers in Shariati Hospital and the Children's Medical Center. Cell culturing including high resolution [HR] and Giemsa banding [G-bands by trypsin using Giemsa strain; GTG] were carried out according to standard protocols. Chromosome analysis was performed following international system for human cytogenetics nomenclature [ISCN] guidelines [1995]. Results-Among the 28 cases, chromosomal abnormality rate was 50% in acute myelogenous leukemia [AML], 80% in acute lymphocytic leukemia [ALL], 83% in chronic myelocytic leukemia [CML] and 100% in the Lymphoproliferative disease [LPD] groups. Two patients in the myeloproliferative disease [MPD]/CML group had normal karyotype and were therefore treated as MPD. The types of observed chromosomal abnormality were translocation 15/17 in AML-M3 patients, double trisomy 8 and 13 in an AML patient, hyperdiploidy of 50- 55 of chromosomes in a child with ALL, a double abnormality of Philadelphia and t 7/8 in a CML patient at blast stage and a complex variant Philadelphia translocation of a t4/9/22 in a CML patient. Conclusion-Despite being a pilot study with a small number of samples, the majority of patients demonstrated chromosomal abnormalities comparable to previously reported cases in other countries. The type of chromosomal abnormality was relevant to diagnosis and stage of the disease