Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterised by abnormal ciliary motion and impaired mucociliary clearance, leading to recurrent respiratory infections, sinusitis, otitis media and male infertility. Some patients also have laterality defects. We recently reported the identification of three disease-causing PCD genes in the Irish Traveller population; RSPH4A, DYX1C1 and CCNO. We have since assessed an additional Irish Traveller family with a complex phenotype involving PCD who did not have any of the previously identified PCD mutations.In this study we report on a family with three children with PCD and various laterality defects. In addition, one child (V:1) has mild-to-moderate developmental delay and one child has speech delay (V:2). Developmental delay is not usually associated with PCD and is likely to be caused by an additional genetic abnormality. Transmission electron microscopy showed variable inner and outer dynein arm defects. Exome sequencing identified a homozygous missense variant in CCDC103 (c.461A > C; p.His154Pro) as the most likely cause of the PCD and laterality defects in this family. However, as mutation in CCDC103 would not account for the developmental delay, array comparative genomic hybridisation was undertaken and identified a maternally inherited gain of ~1.6 Mb (chr17:34,611,352-36,248,918). Gains at this locus are associated with 17q12 duplication syndrome which includes speech and language delay.We report on a variable and complex phenotype caused by the co-inheritance of a single gene mutation in CCDC103 and a microduplication at 17q12, both on chromosome 17. The co-existence of a single gene and chromosome disorder is unusual but accounts for the spectrum of clinical features in this family. In addition, our study brings the total number of PCD genes in the Irish Traveller population to four and we suspect additional PCD genes are yet to be identified. Although, on a global scale, PCD is associated with extensive genetic heterogeneity, finding such a high number of causative PCD genes within the relatively small Irish Traveller population was unexpected.
Hereditary ATM gene mutations cause ataxia-telangiectasia, a pleiotropic disorder associated with a high incidence of lymphoid malignancies. Acquired ATM alterations have been described in sporadic lymphoproliferative disorder suggesting that the ATM gene contributes to lymphomagenesis. To assess the prevalence of genomic ATM alterations in childhood acute lymphoblastic leukemias (ALL), we explored a series of 57 sporadic ALL cases (26 B-precursor ALL and 31 T-ALL) using DHPLC (Denaturing High-Performance Liquid Chromatography). We identified 28 distinct genomic ATM alterations in 14 patients (25%). Ten of them were scored as probably biologically significant and appear to be associated with a high risk of relapse (P<0.01). Six alterations of potential biological significance were observed in 5 cases of B-precursor ALL (19%), while 5 were found in 3 cases of T-ALL (10%). In two cases of B-precursor ALL, the ATM alterations were found in the germline, indicating an ATM carrier status. We report here the high prevalence of genomic ATM alterations in childhood ALL. Our observations lend further support to the postulated contribution of ATM in lymphomagenesis.
Abstract We describe four cases of childhood acute lymphoblastic leukemia with monosomy 20 as the sole cytogenetic abnormality. These cases represent 3.4% of cytogenetically abnormal childhood ALL studied in our institute at diagnosis. The patients presented at similar age, ranging from 31 to 36 months. All four patients remain in first remission with survival time being at least 20 months from the time of diagnosis.
Activation of beta-catenin-mediated transcription is the nuclear end point of organ-specific Wnt signaling. In the developing kidney, Wnt-4, a secreted glycoprotein, acts as an autoinducer of the mesenchymal to epithelial transition that underlies normal nephron development. Dysregulation of this epithelial transformation process may lead to Wilms' tumors (WTs). In this study, we investigated the potential role of the beta-catenin proto-oncogene, a candidate downstream target molecule of Wnt-4 signaling, in the development of WTs. In 6 of 40 tumors (15%), mutation analysis revealed heterozygous missense mutations or small deletions that result in the loss of important regulatory phosphorylation sites within the beta-catenin protein. These findings indicate that activating beta-catenin mutations may play a significant role in the development of WTs and establish a direct link between Wilms' tumorigenesis and the Wnt signal transduction pathway governing normal kidney development.
Acute lymphoblastic leukemia (ALL) of childhood has been cytogenetically well characterized, and approximately 25% of cases will have a high-hyperdiploid (51–68) chromosome complement. In a 5 year period a consecutive series of 152 presentation ALL's were karyotyped. In all cases a result was obtained and 138 (91%) had a detectable abnormal clone of which 44 (29%) were high-hyperdiploid. Within the high-hyperdiploidy group karyotypic cell to cell variation was observed in many cases. To provide further evidence of this phenomenon a dual-color fluorescence in-situ hybridization (FISH) experiment was performed on stored fixed suspension from 14 ALL's with such a karyotype. In each case 4–6 probes were investigated, employing probes to centromeres of chromosomes X, 4, 6, 8, and 10 and a locus specific probe to chromosome 21q22. It was found that the FISH produced results that were generally in good agreement with the G-banding findings and supported the notion of karyotypic cell to cell variation. FISH further showed that most of cases would have two extra copies of chromosome 21 in the majority of leukemic cells and a single extra copy in the minority. A further finding was that fewer cells contained extra copies of chromosomes 6, 8 and 10 than was expected based on the comparison of the signal number of the other probes investigated. In contrast chromosomes X, 4, and 21 seldom displayed this feature. We have demonstrated that karyotypic instability as defined by karyotypic cell to cell variation is a feature of the high-hyperdiploid subgroup in childhood ALL. It is questioned whether the underlying defect resulting in the observed karyotypic instability of this subgroup is one of the primary causative events in the formation of the leukemia.
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