Case Reports – Cyprus Society of Human Genetics (CSHG)

De novo mosaic mutation in a female with Rett syndrome.

istotopos — Sat, 22 Jun 2019 07:51:26 +0000

Abstract
We describe a female with Rett syndrome carrying a rare de novo mosaic nonsense mutation on gene, with random X-chromosome inactivation. Rett syndrome severity in females depends on mosaicism level and tissue specificity, X-chromosome inactivation, epigenetics and environment. Rett syndrome should be considered in both males and females.

GnRH-dependent precocious puberty manifested at the age of 14 months in a girl with 47,XXX karyotype

istotopos — Fri, 19 Oct 2018 14:54:22 +0000

Abstract
This case report describes a 47,XXX girl who presented very early, at the age of 14 months, with signs of sexual precocity (breast and pubic hair development, menarche) and was finally diagnosed with GnRH dependent precocious puberty with no evidence of underlying central nervous system pathology. Molecular testing did not identify any genetic defect in any of the genes tested (KISS1, KISS1R, DLK1 and the intronless MKRN3). Though previous studies have shown a link between karyotype 47,XXX and precocious puberty, this is the youngest patient reported so far. Treatment with GnRH analog was commenced and proved to be effective, indicating a successful suppression of the hypothalamic-pituitary-ovarian axis.

Multiple endocrine neoplasia 2 in Cyprus: evidence for a founder effect.

istotopos — Fri, 19 Oct 2018 14:53:01 +0000

Abstract
PURPOSE:
Multiple endocrine neoplasia type 2 (MEN2) affects patients with RET proto-oncogene mutations. This cohort study refers to patients who were diagnosed with familial medullary thyroid carcinoma (MTC) and underwent RET genetic testing in Cyprus between years 2002 and 2017.METHODS AND PATIENTS:
Forty patients underwent RET testing by Sanger sequencing of exons 10-11 and 13-16. Genotyping with STR genetic markers flanking the RET gene along with Y-chromosome genotyping and haplogroup assignment was also performed.

RESULTS:
RET mutations were identified in 40 patients from 11 apparently unrelated Cypriot families and two non-familial sporadic cases. Nine probands (69.2%) were heterozygous for p.Cys618Arg, one (7.7%) for p.Cys634Phe, one (7.7%) for the somatic delE632-L633 and two (15.4%) for p.Met918Thr mutations. The mean age at MTC diagnosis of patients carrying p.Cys618Arg was 36.8 ± 14.2 years. The age of pheo diagnosis ranged from 26 to 43 years and appeared simultaneously with MTC in 5/36 (13.9%) cases. The high frequency of the p.Cys618Arg mutation suggested a possible ancestral mutational event. Haplotype analysis was performed in families with and without p.Cys618Arg. Six microsatellite markers covering the RET gene and neighboring regions identified one core haplotype associated with all patients carrying p.Cys618Arg mutation.

CONCLUSIONS:
The mutation p.Cys618Arg is by far the most prevalent mutation in Cyprus followed by other reported mutations of variable clinical significance. The provided molecular evidence speculates p.Cys618Arg mutation as an ancestral mutation that has spread in Cyprus due to a possible founder effect.

HIV-1 transmission networks across Cyprus (2010-2012)

istotopos — Fri, 19 Oct 2018 14:50:51 +0000

Abstract
A molecular epidemiology study of HIV-1 infection was conducted in one hundred diagnosed and untreated HIV-1-infected patients in Cyprus between 2010 and 2012, representing 65.4% of all the reported HIV-1 infections in Cyprus in this three-year period, using a previously defined enrolment strategy. Eighty-two patients were newly diagnosed (genotypic drug resistance testing within six months from diagnosis), and eighteen patients were HIV-1 diagnosed for a longer period or the diagnosis date was unknown. Phylogenetic trees of the pol sequences obtained in this study with reference sequences indicated that subtypes B and A1 were the most common subtypes present and accounted for 41.0 and 19.0% respectively, followed by subtype C (7.0%), F1 (8.0%), CRF02_AG (4.0%), A2 (2.0%), other circulating recombinant forms (CRFs) (7.0%) and unknown recombinant forms (URFs) (12%). Most of the newly-diagnosed study subjects were Cypriots (63%), males (78%) with median age 39 (Interquartile Range, IQR 33-48) reporting having sex with other men (MSM) (51%). A high rate of clustered transmission of subtype B drug-sensitive strains to reverse transcriptase and protease inhibitors was observed among MSM, twenty-eight out of forty-one MSM study subjects (68.0%) infected were implicated in five transmission clusters, two of which are sub-subtype A1 and three of which are subtype B strains. The two largest MSM subtype B clusters included nine and eight Cypriot men, respectively, living in all major cities in Cyprus. There were only three newly diagnosed patients with transmitted drug resistant HIV-1 strains, one study subject from the United Kingdom infected with subtype B strain and one from Romania with sub-subtype A2 strain, both with PI drug resistance mutation M46L and one from Greece with sub-subtype A1 with non-nucleoside reverse transcriptase inhibitors (NNRTI) drug resistance mutation K103N.

COL4A5 and LAMA5 variants co-inherited in familial hematuria: digenic inheritance or genetic modifier effect?

istotopos — Fri, 19 Oct 2018 14:49:22 +0000

Abstract
BACKGROUND:
About 40-50% of patients with familial microscopic hematuria (FMH) caused by thin basement membrane nephropathy (TBMN) inherit heterozygous mutations in collagen IV genes (COL4A3, COL4A4). On long follow-up, the full phenotypic spectrum of these patients varies a lot, ranging from isolated MH or MH plus low-grade proteinuria to chronic renal failure of variable degree, including end-stage renal disease (ESRD).METHODS:
Here, we performed Whole Exome Sequencing (WES) in patients of six families, presenting with autosomal dominant FMH, with or without progression to proteinuria and loss of renal function, all previously found negative for severe collagen IV mutations. Hierarchical filtering of the WES data was performed, followed by mutation prediction analysis, Sanger sequencing and genetic segregation analysis.

RESULTS:
In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-p.Pro1243Leu and COL4A5-p.Asp654Tyr. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts.

CONCLUSIONS:
A modifier role of LAMA5 on the background of a hypomorphic Alport syndrome causing mutation is a possible explanation of our findings. Digenic inheritance is another scenario, following the concept that mutations at both loci more accurately explain the spectrum of symptoms, but further investigation is needed under this concept. This is the third report linking a LAMA5 variant with human renal disease and expanding the spectrum of genes involved in glomerular pathologies accompanied by familial hematurias. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced Lama5 protein levels and produced kidney cysts.

Biochemical Characterization of the GBA2 c.1780G>C Missense Mutation in Lymphoblastoid Cells from Patients with Spastic Ataxia

istotopos — Fri, 19 Oct 2018 14:46:46 +0000

Abstract
The GBA2 gene encodes the non-lysosomal glucosylceramidase (NLGase), an enzyme that catalyzes the conversion of glucosylceramide (GlcCer) to ceramide and glucose. Mutations in GBA2 have been associated with the development of neurological disorders such as autosomal recessive cerebellar ataxia, hereditary spastic paraplegia, and Marinesco-Sjogren-Like Syndrome. Our group has previously identified the GBA2 c.1780G>C [p.Asp594His] missense mutation, in a Cypriot consanguineous family with spastic ataxia. In this study, we carried out a biochemical characterization of lymphoblastoid cell lines (LCLs) derived from three patients of this family. We found that the mutation strongly reduce NLGase activity both intracellularly and at the plasma membrane level. Additionally, we observed a two-fold increase of GlcCer content in LCLs derived from patients compared to controls, with the C16 lipid being the most abundant GlcCer species. Moreover, we showed that there is an apparent compensatory effect between NLGase and the lysosomal glucosylceramidase (GCase), since we found that the activity of GCase was three-fold higher in LCLs derived from patients compared to controls. We conclude that the c.1780G>C mutation results in NLGase loss of function with abolishment of the enzymatic activity and accumulation of GlcCer accompanied by a compensatory increase in GCase.

Molecular analysis of Cypriot families with aniridia reveals a novel PAX6 mutation.

istotopos — Fri, 19 Oct 2018 14:41:01 +0000

Abstract
The present study investigated the clinical and mutational spectrum of aniridia in a cohort of 17 affected individuals from six families from Cyprus. Each proband was initially evaluated for copy number variants at the PAX6 locus and subsequently underwent PAX6 mutation screening. Sequence analysis of FOXC1 and PITX2 was performed in patients who did not carry a PAX6 mutation. The most common clinical features in the group of aniridia patients associated with aniridia were nystagmus, cataracts and glaucoma. PAX6 pathogenic mutations were identified in five out of six families (a diagnostic yield of 84%). Previously reported pathogenic mutations in PAX6 were identified in four families, which comprise p.R203*, p.R240* and p.R317*. In addition, a novel pathogenic variant (p.E220Gfs*23) was identified in a single family. No pathogenic mutations were detected in PAX6, FOXC1 or PITX2 in the only patient with a sporadic form of aniridia‑like phenotype, confirming the genetic heterogeneity associated with this disease. To the best of our knowledge this is the first report on the mutational spectrum of PAX6 in aniridia patients of Cypriot ancestry. Mutational screening of PAX6 serves a crucial role in distinguishing isolated from syndromic forms of aniridia, and it may therefore eliminate the need for renal ultrasound scan surveillance, delineate the phenotype and improve genetic counseling.

Eleven cases of sickle cell disease in Sydney.

istotopos — Tue, 21 Aug 2018 13:47:14 +0000

Abstract
Eleven cases of sickle cell disease within the Sydney area are described. Eight of these are of homozygous sickle cell anaemia, and three are of the sickle cell-thalassaemia disease. The racial origin is Lebanese Moslem in five cases, Greek from the mainland or Cyprus in four, and Portuguese, French, and Spanish in two sisters: consanguinity occurred in the latter family, and in three of the five Lebanese Moslem families. The age of patients at diagnosis ranged from five months to 22 years, and the clinical severity from very mild to very severe, with a wide spectrum of clinical manifestations. It is concluded that sickle cell disease is already a significant health problem within the Sydney area, and likely to increase in incidence with increasing migration from endemic zones.

The molecular basis for the haemoglobin Bart’s hydrops fetalis syndrome in Cyprus.

istotopos — Tue, 21 Aug 2018 13:47:14 +0000

Molecular basis for mild forms of homozygous beta-thalassaemia.

istotopos — Tue, 21 Aug 2018 13:47:14 +0000

Abstract
Five Cypriots homozygous for beta +-thalassaemia have inherited deletion or non-deletion forms of alpha-thalassaemia that seem to have modified the usually severe clinical picture to that of mild thalassaemia intermedia. These observations have important implications for the antenatal diagnosis of beta-thalassaemia.