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Smith–Magenis syndrome is a complex neurobehavioral genetic disorder with a broad phenotypic spectrum. While the etiology of SMS is commonly attributed to one-copy interstitial deletion in the 17p11.2 region (90–95% of cases), variants identified by sequence analysis in RAI1 have also been reported in 5–10% of cases. In this study, we report a 9-year-old male with global cognitive and psychomotor developmental delay, musculoskeletal and cardiovascular abnormalities, and dysmorphic craniofacial features. Joint analysis was performed on the whole-genome sequencing data obtained from the proband, unaffected parents, and unaffected brother. This quad analysis identified the novel de novo RAI1:c.2736delC variant. This is the first report of this variant in the literature. This report highlights the details of genome analysis and the patient's phenotypic spectrum. [ABSTRACT FROM AUTHOR]

Purpose: An investigation for the co-occurrence of two unrelated genetic disorders of muscular dystrophy and Prader-Willi syndrome (PWS) (OMIM#176270) using joint whole genome sequencing (WGS). Methods: Trio WGS joint analysis was performed to investigate the genetic etiology in a proband with PWS, prolonged muscular hypotonia associated hyperCKemia, and early-onset obesity. The parents were unaffected. Results: Results showed maternal isodisomy uniparental disomy (UPD) in chromosome 15, expanding from 15q11.2 to 15q22.2, including PWS regions at 15q11.2–15q13. Maternal heterodisomy was detected from 15q22.2 to 15q26.3. A pathogenic variant, NM_000070.3(CAPN3):c.550del (p.Thr184fs), was identified at 15q15.1 in a heterozygous state in the mother that was homozygous in the proband due to maternal isodisomy. Conclusion: This is the first study of the concurrent molecular etiology of PWS and calpainopathy (OMIM#253600) in the same patient. This report highlights the utility of joint analysis and the need for the assessment of autosomal recessive disease in regions of isodisomy in patients with complex and unexplained phenotypes. [ABSTRACT FROM AUTHOR]

Aim: The purpose of this case-control study was to assess the association of abdominal aortic aneurysm (AAA) in Croatian patients with four genetic polymorphisms: SNP 1166A>C in the angiotensin II type 1 receptor gene ( AT1R); SNP -1562C>T in the matrix metalloproteinase-9 gene ( MMP-9); the deletion of 32 bp in the chemokine receptor 5 gene ( CCR5); and the insertion/deletion (I/D) of 287 bp in the angiotensin-converting enzyme gene ( ACE). Methods: Case-control study conducted with 117 patients with confirmed AAA (AAA+) and 117 control subjects (AAA−). Genotyping was performed using PCR or PCR-RFLP analysis. Statistical analyses were performed using MedCalc 12.1 software. Results: The deletion of 287 bp in the ACE gene (allele D) was more frequently found among AAA+ patients than AAA− subjects (66.7% vs. 47.9%, p = 0.0001), due principally to a higher percentage of DD homozygotes (46.2% vs. 15.4%, p < 0.0001). The associated increased risk for AAA was detected in both the nonadjusted recessive model of inheritance (odds ratio [OR] = 3.00, 95% confidence interval [CI] = 1.88-4.79, p = < 0.0001) and when adjusted for age, sex, smoking, hypertension, and hyperlipidemia (OR = 4.96; 95% CI = 1.68-14.59, p = 0.004). The adjusted recessive models also showed increased risk for AAA for the carriers of MMP-9 T allele (OR = 15.69, 95% CI = 1.40-175.41, p = 0.025). Patients with small aneurysms compared with those with large ones were more frequent carriers of the AT1R allele C (37.8% vs. 23.2%, p = 0.029), and logistic regression analysis showed decreased risk for developing large aneurysms in both adjusted models, dominant and recessive (OR = 0.3929, 95% CI = 0.1554-0.9932, p = 0.0483 and OR = 0.1728, 95% CI = 0.0331-0.9023; p = 0.0374, respectively). No difference among any type of the studied groups or subgroups was observed regarding the CCR5Δ32 polymorphism. Conclusions: ACE I/D is associated with AAA, and 1166A>C AT1R with the size of the aneurysm, while -1562C>T MMP-9 and CCR5Δ32 polymorphisms are most probably not associated with AAA in Croatian patients. [ABSTRACT FROM AUTHOR]

The largest proportion of all chromosomal anomalies in humans are syndromes Down (trisomy of chromosome 21), Edwards (trisomy of chromosome 18) and Patau (trisomy of chromosome 13). This fact has revealed the need to introduce methods that would allow rapid diagnosis of the most common numerical chromosomal abnormalities, which is of special importance in prenatal diagnosis. Analysis of the microsatellite or STR locus with the PCR-STR method has given us the possibility of fast diagnosis of the most frequent aneuploidies within one to three days. The advantage of the analysis of STR loci in prenatal and postnatal diagnosis lies in the ability to determine the origin of chromosomes in the diagnosis of uniparental disomy. At the Zagreb University Hospital Centre, rapid prenatal and postnatal diagnosis of aneuploidy and uniparental disomy was performed using analysis of the microsatellite loci of chromosomes 7, 11, 13, 14, 15, 18, 21, X and Y. The purpose of the work was to show diagnostic value of the microsatellite loci on the above listed chromosomes. On prenatal screening of 2072 amniotic fluid samples, 55 (2.65%) showed change in the number of chromosomes. As expected, the largest number of samples (n=35) showed trisomy of chromosome 21. Uniparental disomy of chromosome 15 (UPD15) was demonstrated in 13 of 54 subjects with suspicion of uniparental disomy. The results of the PCR-STR method were in accordance with the results of conventional cytogenetics. In conclusion, the combination of STR loci that we use is considered good enough to determine aneuploidy of chromosomes 13, 18, 21, X and Y, and uniparental disomy of chromosomes 7, 11, 14 and 15. [ABSTRACT FROM AUTHOR]

Aim To determine the value of short-tandem repeat markers on the chromosome X (X-STR) for prenatal diagnostics of the chromosome X numerical disorders. Methods We investigated the genetic variability of 5 Xmarkers (DXS9895, DXS6810, DXS6803, GATA172D05, and HPRTB) in 183 healthy Croatian individuals (90 men and 93 women). We also tested 13 patients with X chromosome disorders (Turner syndrome - 6 cases; Klinefelter syndrome - 5 cases, and Triple X syndrome - 2 cases). The analysis was performed using polymerase chain reaction amplification with specific primers and electrophoresis on a polyacrylamide gel. The study was performed in 2010. Results Our sample showed no significant differences in allelic frequencies of the investigated X-markers from other European populations. A set of 5 X-STR markers was sufficiently informative for a successful determination of the chromosome X numerical abnormalities. Conclusion Since no false positive or negative results were observed, diagnostic value of the investigated X-STR loci for prenatal detection of chromosome X numerical disorders was confirmed. Our study represents an important step toward an improved prenatal diagnostics in Croatia. [ABSTRACT FROM AUTHOR]

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Aim: The purpose of this case-control study was to assess the association of abdominal aortic aneurysm (AAA) in Croatian patients with four genetic polymorphisms: SNP 1166A>C in the angiotensin II type 1 receptor gene (AT 1 R); SNP -1562C>T in the matrix metalloproteinase-9 gene (MMP-9); the deletion of 32 bp in the chemokine receptor 5 gene (CCR5); and the insertion/deletion (I/D) of 287 bp in the angiotensin-converting enzyme gene (ACE)., Methods: Case-control study conducted with 117 patients with confirmed AAA (AAA + ) and 117 control subjects (AAA - ). Genotyping was performed using PCR or PCR-RFLP analysis. Statistical analyses were performed using MedCalc 12.1 software., Results: The deletion of 287 bp in the ACE gene (allele D) was more frequently found among AAA + patients than AAA - subjects (66.7% vs. 47.9%, p = 0.0001), due principally to a higher percentage of DD homozygotes (46.2% vs. 15.4%, p < 0.0001). The associated increased risk for AAA was detected in both the nonadjusted recessive model of inheritance (odds ratio [OR] = 3.00, 95% confidence interval [CI] = 1.88-4.79, p = < 0.0001) and when adjusted for age, sex, smoking, hypertension, and hyperlipidemia (OR = 4.96; 95% CI = 1.68-14.59, p = 0.004). The adjusted recessive models also showed increased risk for AAA for the carriers of MMP-9 T allele (OR = 15.69, 95% CI = 1.40-175.41, p = 0.025). Patients with small aneurysms compared with those with large ones were more frequent carriers of the AT 1 R allele C (37.8% vs. 23.2%, p = 0.029), and logistic regression analysis showed decreased risk for developing large aneurysms in both adjusted models, dominant and recessive (OR = 0.3929, 95% CI = 0.1554-0.9932, p = 0.0483 and OR = 0.1728, 95% CI = 0.0331-0.9023; p = 0.0374, respectively). No difference among any type of the studied groups or subgroups was observed regarding the CCR5Δ32 polymorphism., Conclusions: ACE I/D is associated with AAA, and 1166A>C AT 1 R with the size of the aneurysm, while -1562C>T MMP-9 and CCR5Δ32 polymorphisms are most probably not associated with AAA in Croatian patients.