Multiple malformation syndromes (MMS) belong to a group of genetic disorders characterised by neurodevelopmental anomalies and congenital malformations. Here we explore for the first time the genetic ...aetiology of MMS using whole-exome sequencing (WES) in undiagnosed patients from the Greek-Cypriot population after prior extensive diagnostics workup including karyotype and array-CGH. A total of 100 individuals (37 affected), from 32 families were recruited and family-based WES was applied to detect causative single-nucleotide variants (SNVs) and indels. A genetic diagnosis was reported for 16 MMS patients (43.2%), with 10/17 (58.8%) of the findings being novel. All autosomal dominant findings occurred de novo. Functional studies were also performed to elucidate the molecular mechanism relevant to the abnormal phenotypes, in cases where the clinical significance of the findings was unclear. The 17 variants identified in our cohort were located in 14 genes (PCNT, UBE3A, KAT6A, SPR, POMGNT1, PIEZO2, PXDN, KDM6A, PHIP, HECW2, TFAP2A, CNOT3, AGTPBP1 and GAMT). This study has highlighted the efficacy of WES through the high detection rate (43.2%) achieved for a challenging category of undiagnosed patients with MMS compared to other conventional diagnostic testing methods (10-20% for array-CGH and ~3% for G-banding karyotype analysis). As a result, family-based WES could potentially be considered as a first-tier cost effective diagnostic test for patients with MMS that facilitates better patient management, prognosis and offer accurate recurrence risks to the families.
Steel syndrome is an autosomal recessive disorder that primarily affects the skeletal system causing a variety of manifestations. Sixteen individuals with Steel syndrome, mainly Puerto Ricans ...(11/16), were previously reported to carry bi-allelic mutations in the COL27A1 gene. Here, we present the first patient with Steel syndrome in Europe and the sixth non-Puerto Rican carrying a novel homozygous mutation in COL27A1. The patient is a 4-year-old boy born to non-consanguineous healthy parents, with dysmorphic facial features, absent hip ossification centres, external rotation of both feet, relatively short stature, mild skin syndactyly, short mid phalanges and bilateral sensorineural hearing loss. Whole exome sequencing (WES) revealed a novel homozygous missense variant p.(Gly802Glu) in COL27A1. The homozygous mutation was confirmed by Sanger sequencing in the proband and carrier status was confirmed in both parents and his unaffected sibling. According to online and in-house minor allele frequency (MAF) databases, this is the first COL27A1 mutation reported in the European population. Additional screening of healthy Greek-Cypriot individuals was thus performed, which did not reveal any additional carriers in the population for the variant in question.
Cyprus maintains a population-based cancer registry that allows for in-depth study of cancer in a culturally and environmentally unique setting. Using 11 years of collected data (1998-2008), we ...present the first comprehensive analysis of cancer in Cyprus. We calculated gender-specific, world age-adjusted incidence rates and time trends for the 26 most incident cancers. This study revealed that overall world age-standardized rates among men increased from 195.4 cases per 100,000 in 1998-2002 to 239.0 cases per 100,000 in 2006-2008. For the entire 11-year period, prostate, lung, colorectal and bladder cancers were the most incident cancers among men. Among women, the overall world age-standardized rate increased from 180.6 cases per 100,000 in 1998-2002 to 217.1 cases per 100,000 in 2006-2008. Over the entire period, breast, colorectal, uterine and thyroid cancers were the most incident cancers in women. There were 16 sex-specific cancers showing statistically significantly increasing incidence trends over the study period and no types for which the rate was significantly decreasing. Thyroid cancer illustrated rapid increases in rates. Results were compared to other Mediterranean European registries using the Cancer Incidence in 5 Continents reports for 1997-2002. Overall cancer incidence in Cyprus is lower than that of many southern Mediterranean countries, and given the known environmental risk factors in Cyprus, the low rate of lung cancer is especially interesting. The epidemiologic patterns reported in this study open the door for future etiologic studies to elucidate the role of environmental and lifestyle factors in this population and highlight opportunities for cancer prevention and control.
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