Kairit Joost

The live-birth prevalence of mucopolysaccharidoses in Estonia

Previous studies on the prevalence of mucopolysaccharidoses (MPS) in different populations have shown considerable variations. There are, however, few data with regard to the prevalence of MPSs in Fenno-Ugric populations or in north-eastern Europe, except for a report about Scandinavian countries. A retrospective epidemiological study of MPSs in Estonia was undertaken, and live-birth prevalence of MPS patients born between 1985 and 2006 was estimated. The live-birth prevalence for all MPS subtypes was found to be 4.05 per 100,000 live births, which is consistent with most other European studies. MPS II had the highest calculated incidence, with 2.16 per 100,000 live births (4.2 per 100,000 male live births), forming 53% of all diagnosed MPS cases, and was twice as high as in other studied European populations. The second most common subtype was MPS IIIA, with a live-birth prevalence of 1.62 in 100,000 live births. With 0.27 out of 100,000 live births, MPS VI had the third-highest live-birth prevalence. No cases of MPS I were diagnosed in Estonia, making the prevalence of MPS I in Estonia much lower than in other European populations. MPSs are the third most frequent inborn error of metabolism in Estonia after phenylketonuria and galactosemia.

Hearing impairment in Estonia: An algorithm to investigate genetic causes in pediatric patients

PURPOSE The present study was initiated to establish the etiological causes of early onset hearing loss (HL) among Estonian children between 2000-2009. METHODS The study group consisted of 233 probands who were first tested with an arrayed primer extension assay, which covers 199 mutations in 7 genes (GJB2, GJB6, GJB3, SLC26A4, SLC26A5 genes, and two mitochondrial genes - 12S rRNA, tRNASer(UCN)). From probands whose etiology of HL remained unknown, DNA analysis of congenital cytomegalovirus (CMV) infection and G-banded karyotype and/or chromosomal microarray analysis (CMA) were performed. RESULTS In 110 (47%) cases, the etiology of HL was genetic and in 5 (2%) congenital CMV infection was diagnosed. We found mutations with clinical significance in GJB2 (100 children, 43%) and in 2 mitochondrial genes (2 patients, 1%). A single mutation in SLC26A4 gene was detected in 5 probands (2.2%) and was considered diagnostic. In 4 probands a heterozygous IVS2-2A>G change in the SLC26A5 gene was found. We did not find any instances of homozygosity for this splice variant in the probands. CMA identified in 4 probands chromosomal regions with the loss of one allele. In 2 of them we were able to conclude that the found abnormalities are definitely pathogenic (12q13.3-q14.2 and 17q22-23.2 microdeletion), but the pathogenity of 2 other findings (3p26.2 and 1p33 microdeletion) remained unknown. CONCLUSION This practical diagnostic algorithm confirmed the etiology of early onset HL for 115 Estonian patients (49%). This algorithm may be generalized to other populations for clinical application.

The Frequency of Methylation Abnormalities Among Estonian Patients Selected by Clinical Diagnostic Scoring Systems for Silver–Russell Syndrome and Beckwith–Wiedemann Syndrome

AIMS To study the frequency of methylation abnormalities among Estonian patients selected according to published clinical diagnostic scoring systems for Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS). MATERIALS AND METHODS Forty-eight patients with clinical suspicion of SRS (n = 20) or BWS (n = 28) were included in the study group, to whom methylation-specific multiplex ligation-dependant probe amplification analysis of 11p15 region was made. In addition, to patients with minimal diagnostic score for either SRS or BWS, multilocus methylation-specific single nucleotide primer extension assay was performed. RESULTS Five (38%) SRS patients with positive clinical scoring had abnormal methylation pattern at chromosome 11p15, whereas in the BWS group, only one patient was diagnosed with imprinting control region 2 (ICR2) hypomethylation (8%). An unexpected hypomethylation of the PLAGL1 (6q24) and IGF2R (6q25) genes in the patient with the highest BWS scoring was found. CONCLUSIONS Compared to BWS, diagnostic criteria used for selecting SRS patients gave us a similar detection rate of 11p15 imprinting disorders as seen in other studies. A more careful selection of patients with possible BWS should be considered to improve the detection of molecularly confirmed cases. Genome-wide multilocus methylation tests could be used in routine clinical practice as it increases the detection rates of imprinting disorders.

De novo exonic mutation in MYH7 gene leading to exon skipping in a patient with early onset muscular weakness and fiber-type disproportion

Here we report on a case of MYH7-related myopathy in a boy with early onset of muscular weakness and delayed motor development in infancy. His most affected muscles were neck extensors showing a dropped head sign, proximal muscles of lower limbs with positive Gowers sign, and trunk muscles. Brain and spinal cord MRI scans, echocardiography, and laboratory analyses including creatine kinase and lactate did not reveal any abnormalities. Muscle histopathology showed fiber-type disproportion. Whole exome sequencing of the parents-offspring trio revealed a novel de novo c.5655G>A p.(Ala1885=) synonymous substitution of the last nucleotide in exon 38 of the MYH7 gene. Further RNA investigations proved the skipping of exon 38 (p.1854_1885del). This is a first report of an exon-skipping mutation in the MYH7 gene causing myopathy. This report broadens both the phenotypic and genotypic spectra of MYH7-related myopathies.

Kuulmislanguse geneetilised põhjused Eesti lastel ning leitud genotüübi ja fenotüübi omavaheline võrdlus

Eesmark. Selgitada valja kuulmislanguse (KL) geneetilised pohjused Eesti lastel ja kirjeldada nende fenotuupi. Metoodika. Uuringus osales 233 KLiga last, kellele tehti APEX-geenikiibi analuus 201 erineva mutatsiooni suhtes 8 parilikku KLi pohjustavas geenis (GJB2, GJB3, GJB6, GJA1, SLC26A4, SLC26A5, 12S-rRNA ja tRNA (Ser) geenid). Tulemused. Leidsime 115 patsiendil (49%) GJB2 mutatsiooni vahemalt uhes alleelis, neist 100 lapsel esines vahemalt uhes alleelis mutatsioon c.35delG. 5 patsiendi (2%) KL oli tingitud kaasasundinud tsutomegalovi irusinfektsioonist. Sundroomne KL kinnitati 7 uuritaval. Kogu genoomi genotupiseerimisplatformi analuus tehti 28 patsiendile, selle tulemusel leidsime 4 erinevat potentsiaalselt patogeenset deleteerunud kromosoomipiirkonda. Jareldused. Koige sagedasem lapseea KLi pohjustav mutatsioon on c.35delG, mille osakaal KLiga laste hulgas on 75% GJB2 geeni mutatsioonidest. Uuringu tulemusena selgus voi tapsustus KLi etioloogias geneetiline faktor 140 patsiendil (60%). Eesti Arst 2010; 89(12):781−789

Pärilik ehk geneetiline kuulmislangus

Kuulmislangus on koige enam levinud sensoorne haigus kogu maailmas. Varajase ehk kone-eelse kuulmislanguse esinemissagedus arvatakse olevat 1–2 juhtu 1000 lapse kohta ning pooltel juhtudest on see parilik. Geneetiline kuulmislangus jagatakse sundroomseks vormiks, mille korral kuulmislangus on seotud teiste elundite anomaaliatega, ja mittesundroomseks ehk isoleeritud vormiks. Eesti Arst 2007; 86 (4): 254–261