Two novel mutations in the DNAH11 gene in primary ciliary dyskinesia (CILD7) with considerable variety in the clinical and beating cilia phenotype.

BACKGROUND: Diagnosis of primary ciliary dyskinesia (PCD) still remains a challenge, especially with mutations in the Dynein Arm Heavy Chain 11 (DNAH11) gene. Classical diagnostic measures like Transmission Electron Microscopy (TEM) are not applicable for mutations in the DNAH11 gene since ultrastructural defects of the ciliary apparatus are absent. Novel mutations encoding for PCD appear all the time with considerable variation in the clinical picture, making it necessary to update data bases and guidelines for PCD diagnostics. METHODS: In this study we examined two unrelated, Finnish families with symptoms of PCD applying the clinical scoring system: Primary ciliary dyskinesia Rule (PICADAR), high speed video microscopy analysis (HSVMA) for ciliary movement, a commercially available gene panel analysis and nasal Nitric Oxide (nNO) measurements if applicable. RESULTS: Two, likely pathogenic variants in the DNAH11 gene (c.2341G > A, p. (Glu781Lys) ja c.7645 + 5G > A) were detected. In the first family, compound heterozygous mutations led to disease manifestation in two of 4 children, which showed a similar phenotype of cilia beating pattern but marked differences in disease severity. In the second family, all three children were homozygotes for the c.2341G > A p.(Glu781Lys) mutation and showed a similar degree of disease severity. However, the phenotype of cilia beating pattern was different ranging from stiff, static cilia to a hyperkinetic movement in one of these children. CONCLUSIONS: In this study we describe two Finnish families with PCD, revealing two novel mutations in the DNAH11 gene which show considerable variety in the clinical and beating cilia phenotype. The results of this study show the clinician that PCD can be much milder than generally expected and diagnosis demands a combination of measures which are only successful in experienced hands. Chronic and repeatedly treated wet cough should raise suspicion of PCD, referring the patient for further diagnostics to a specialised PCD centre.

Genetic testing and new variants in diagnosis of congenital ichthyoses.

BACKGROUND: The aim of this study was to evaluate how diagnostic practice in congenital ichthyoses has evolved during the years 2000-2020 and what kind of gene variants of congenital ichthyosis have been found. METHODS: The study cohort of this register-based research consisted of a total of 88 patients, whose diagnostic testing was conducted, and ichthyosis diagnoses set at the Department of Dermatology and the Department of Clinical Genetics at Tampere University Hospital during the years 2000-2020. RESULTS: Diagnosis of ichthyosis was confirmed with genetic testing in 33 cases, and with conventional diagnostic methods, such as clinical findings, skin biopsy and family history of ichthyoses, in 55 cases. We observed four novel variants in patients with the clinical diagnoses of congenital ichthyoses. CONCLUSION: When genetic testing became available, it was offered primarily to patients with severe forms of ichthyosis. During the study period next-generation sequencing became the genetic testing method of choice providing new opportunities in diagnostics.

Genetic testing for familial hypercholesterolemia in a Finnish cohort of patients with premature coronary artery disease and elevated LDL-C levels.

Background: Based on Finnish LDLR-founder variations, the prevalence of familial hypercholesterolemia (FH) in Finland is estimated to be at least 1:600. Patients with FH have increased risk of premature coronary artery disease (CAD) and thus the prevalence of FH is expected to be higher in this subgroup. Objective: To assess the prevalence of monogenic FH in a Finnish cohort of patients with premature CAD and elevated low-density lipoprotein cholesterol (LDL-C) levels. Methods: Among 28,295 patients undergoing angiography at Heart Hospital at Tampere University Hospital between 2007 and 2017, we identified 162 patients diagnosed with premature CAD (men aged <55 years and women aged <60 years) and history of high LDL-C (≥5 mmol/L) levels without secondary causes of hypercholesterolemia. Clinical probability of FH was estimated, and genetic testing of FH was carried out in 80 patients with informed consent. Results: Of the 80 patients with premature CAD and history of high LDL-C levels, 70% were men; the age at diagnosis of CAD for male and female patients was 48 and 53 years, respectively. In total, 58 (73%) patients had probable (n = 54) or definite (n = 4) FH based on Dutch Lipid Clinic Network criteria. A pathogenic variant of FH was found in five (6%) patients. Prevalence of the genetically verified FH was 1:16. The FH variant was found in 75% of patients with definite FH. Conclusions: The prevalence of genetically verified FH was 1:16 among patients with premature CAD and elevated LDL-C level, which is 38 times higher than the estimated prevalence of 1:600 in the general Finnish population.

Associations of polygenic risk scores for preeclampsia and blood pressure with hypertensive disorders of pregnancy.

BACKGROUND: Preexisting hypertension increases risk for preeclampsia. We examined whether a generic blood pressure polygenic risk score (BP-PRS), compared with a preeclampsia-specific polygenic risk score (PE-PRS), could better predict hypertensive disorders of pregnancy. METHODS: Our study sample included 141 298 genotyped FinnGen study participants with at least one childbirth and followed from 1969 to 2021. We calculated PRSs for SBP and preeclampsia using summary statistics for greater than 1.1 million single nucleotide polymorphisms. RESULTS: We observed 8488 cases of gestational hypertension (GHT) and 6643 cases of preeclampsia. BP-PRS was associated with GHT [multivariable-adjusted hazard ratio for 1SD increase in PRS (hazard ratio 1.38; 95% CI 1.35-1.41)] and preeclampsia (1.26, 1.23-1.29), respectively. The PE-PRS was also associated with GHT (1.16; 1.14-1.19) and preeclampsia (1.21, 1.18-1.24), but with statistically more modest magnitudes of effect (P = 0.01). The model c-statistic for preeclampsia improved when PE-PRS was added to clinical risk factors (P = 4.6 × 10-15). Additional increment in the c-statistic was observed when BP-PRS was added to a model already including both clinical risk factors and PE-PRS (P = 1.1 × 10-14). CONCLUSION: BP-PRS is strongly associated with hypertensive disorders of pregnancy. Our current observations suggest that the BP-PRS could capture the genetic architecture of preeclampsia better than the current PE-PRSs. These findings also emphasize the common pathways in the development of all BP disorders. The clinical utility of a BP-PRS for preeclampsia prediction warrants further investigation.

Role of an automated screening tool for familial hypercholesterolemia in patients with premature coronary artery disease.

Background and aims: To validate an automated screening tool for patients with premature coronary artery disease (CAD) and high total cholesterol or LDL-C levels and assess if it would provide clinicians with additional support in identifying patients with Familial Hypercholesterolemia (FH). Methods: An IT-based automated screening tool based on coronary angiography data recorded in the KARDIO registry and laboratory values was validated among patients undergone coronary angiography in the Heart Hospital at Tampere University Hospital between 2007 and 2017 fulfilling the criteria of premature CAD (men <55 years and women <60 years) and history of high total cholesterol (>8 mmol/l) or LDL-cholesterol (>5 mmol/l) levels. Electronic health records were retrospectively analyzed to determine if these patients had been diagnosed with FH based on clinical features and whether genetic testing had been conducted. Results: The automated screening tool identified 0.7% (211/28295) of all patients undergone coronary angiography and revealed history of high cholesterol in 8% (211/2678) of patients with premature CAD during the study period. Fifty-one percent (107/211) of these patients fulfilled the clinical criteria for probable/definite FH based on the Dutch Lipid Clinic Network (DLCN) criteria.None of the patients had been diagnosed with FH based on clinical criteria before or after diagnosis of CAD. Thirteen percent of patients (n = 14) with probable/definite FH had been tested for genetic mutations of FH before or after CAD, five (36%) of them having a pathogenic FH variant. Two patients were referred to cascade screening. Conclusions: FH was underdiagnosed among the population studied. An automated screening tool in cardiac care could provide additional support for clinicians in diagnosing patients potentially having FH.

Increased Risk of Preeclampsia in Women With a Genetic Predisposition to Elevated Blood Pressure.

BACKGROUND: Preeclampsia causes significant maternal and perinatal morbidity. Genetic factors seem to affect the onset of the disease. We aimed to investigate whether the polygenic risk score for blood pressure (BP; BP-PRS) is associated with preeclampsia, its subtypes, and BP values during pregnancy. METHODS: The analyses were performed in the FINNPEC study (Finnish Genetics of Pre-Eclampsia Consortium) cohort of 1514 preeclamptic and 983 control women. In a case-control setting, the data were divided into percentiles to compare women with high BP-PRS (HBP-PRS; >95th percentile) or low BP-PRS (≤5th percentile) to others. Furthermore, to evaluate the effect of BP-PRS on BP, we studied 3 cohorts: women with preeclampsia, hypertensive controls, and normotensive controls. RESULTS: BP values were higher in women with HBP-PRS throughout the pregnancy. Preeclampsia was more common in women with HBP-PRS compared with others (71.8% and 60.1%, respectively; P=0.009), and women with low BP-PRS presented with preeclampsia less frequently than others (44.8% and 61.5%, respectively; P<0.001). HBP-PRS was associated with an increased risk for preeclampsia (odds ratio, 1.7 [95% CI, 1.1-2.5]). Furthermore, women with HBP-PRS presented with recurrent preeclampsia and preeclampsia with severe features more often. CONCLUSIONS: Our results suggest that HBP-PRS is associated with an increased risk of preeclampsia, recurrent preeclampsia, and preeclampsia with severe features. Furthermore, women with HBP-PRS present higher BP values during pregnancy. The results strengthen the evidence pointing toward the role of genetic variants associated with BP regulation in the etiology of preeclampsia, especially its more severe forms.

Adiponectin gene haplotype is associated with preeclampsia.

We determined whether the polymorphism of the gene encoding adiponectin contributes to susceptibility to preeclampsia. The study involved 133 Finnish women with preeclampsia and 245 healthy control subjects. All women were genotyped for two single nucleotide polymorphisms (SNPs), SNP45 in exon 2 and SNP276 in intron 2, in the adiponectin gene. Chi2 analysis was used to assess genotype and allele frequency differences between the preeclamptic and control groups. In addition, the pair of loci haplotype analysis, using the expectation-maximization (EM) algorithm, was used to examine the estimated haplotype frequencies of the two SNPs, among the two groups. The TT genotype versus the pooled G genotypes in SNP276 was associated with protection against preeclampsia (p = 0.012) at an odds ratio of 0.27 (95% confidence interval [CI]: 0.09-0.80). Also the genotype and allele frequency distributions of SNP276 differed significantly between the preeclampsia group and the control group (p = 0.035 and p = 0.043, respectively). Single-point genotype and allele distributions in SNP45 of the adiponectin gene were not statistically different between the groups. In the haplotype estimation analysis, the pooled G haplotypes versus the TT haplotype were significantly overrepresented in the preeclampsia group (p = 0.042 +/- 0.005). Polymorphisms of the adiponectin gene show a weak, but statistically significant, haplotype association with susceptibility to preeclampsia in Finnish women.

Polymorphisms of interleukin-6, hepatic lipase and calpain-10 genes, and preeclampsia.

OBJECTIVE: We determined whether single nucleotide polymorphisms (SNPs) in interleukin-6 (IL-6), hepatic lipase (HL) and calpain-10 (CAPN-10) genes contribute to susceptibility to develop preeclampsia. STUDY DESIGN: The study involved 133 preeclamptic and 115 healthy pregnant women who were genotyped for the C-174G polymorphism in the IL-6 gene, the G-250A polymorphism in the HL gene and SNP 43 (G/A) in the CAPN-10 gene. The chi2-test was used to assess genotype and allele frequency differences between the preeclamptic and control groups. RESULTS: No significant differences were detected in genotype and allele distributions of the C-174G polymorphism in the IL-6 gene, between the preeclampsia and control groups (p=0.98 and 0.85, respectively). With respect to the G-250A polymorphism in the HL gene, the genotype and allele distributions were similar in both groups (p=0.64 and 0.48, respectively). The genotype and allele distributions of SNP 43 in the CAPN-10 gene also showed no statistical differences in the preeclampsia and control groups (p=0.73 and 0.45, respectively). CONCLUSIONS: The C-174G polymorphism in the IL-6 gene, the G-250A polymorphism in the HL gene and SNP 43 (G/A) in the CAPN-10 gene are unlikely to be major genetic factors predisposing Finnish women to preeclampsia.

Plasma cell membrane glycoprotein-1 K121Q polymorphism in preeclampsia.

BACKGROUND: Preeclampsia is a common hereditary disease with unclear aetiology and various genetic and environmental components. We wanted to determine whether genetic variability in the gene encoding plasma cell membrane glycoprotein-1 (PC-1) contributes to individual susceptibility to the development of preeclampsia. METHODS: The case-control study involved 133 women with preeclampsia and 115 healthy controls. They were genotyped for the K121Q polymorphism in the PC-1 gene. chi(2) analysis was used to assess genotype and allele frequency differences between preeclamptic and control women. RESULTS: The frequency of the PC-1 gene 121K allele was found to be equal in the two groups, being 90.2% among women with preeclampsia and 90.4% among controls (p = 0.937; OR = 1.024; 95% CI = 0.564-1.861). Also the genotype distribution of the PC-1 K121Q polymorphism was similar (p = 0.516) in the preeclamptic and control groups. CONCLUSIONS: The K121Q polymorphism of the PC-1 gene is unlikely to be a major genetic factor predisposing to preeclampsia in Finnish women.

Preeclampsia and androgen receptor gene CAG repeat length: results from both children and women.

PURPOSE: We studied whether the CAG (encoding glutamine) repeat length polymorphism in the first exon of the androgen receptor (AR) gene is predictive of preeclampsia. METHODS: Fifty-nine children born after preeclamptic pregnancy (PRE) and 58 control subjects born after normotensive pregnancy (non-PRE) were genotyped for the CAG repeat length of the AR gene. Secondly, the ARCAG repeat lengths of 133 unrelated preeclamptic women and 112 healthy controls were studied. The mean AR gene CAG lengths were compared between the preeclampsia and the control groups. RESULTS: The mean length of the CAG repeat segment among children was significantly shorter in the PRE group compared with the non-PRE group (p = 0.02). Interestingly, the difference between the PRE and the non-PRE boys was even more significant (p = 0.008). Also the distribution of allele frequencies was different, short repeat lengths being overrepresented in the PRE children. However, there were no significant differences in the mean CAG repeat lengths between the unrelated preeclamptic women and their controls, but the shortest CAG repeat lengths were found only in the preeclamptic women. CONCLUSIONS: The AR gene CAG repeat length is not a major determinant in the development of preeclampsia. The association of the shortest CAG repeats with preeclampsia is possible, but a larger study group is needed to confirm this finding.

Tumour necrosis factor-alpha gene haplotype is associated with pre-eclampsia.

We determined whether polymorphisms in the promoter region of the tumour necrosis factor alpha (TNF-alpha) gene contributes to differences in susceptibility to develop pre-eclampsia. The study involved 133 pre-eclamptic and 115 healthy pregnant women who were genotyped for the G-308A polymorphism of the TNF-alpha gene. The frequency of the G-308A allele was more common in the pre-eclampsia group than among the controls (P=0.046), giving an odds ratio of 0.57 (95% CI: 0.32-0.99), but there were no differences in the genotype distribution. The data from the G-308A polymorphism was combined with the previously published genotype and allele data from the C-850T polymorphism of the TNF-alpha gene, and used to assess a haplotype estimation analysis. Estimated overall pair of loci haplotype frequencies differed significantly between the groups (P=0.023+/-0.004). In the single haplotype association analysis, the haplotype C-A versus others was over-represented in the pre-eclampsia group (P=0.041+/-0.003), whereas the haplotype T-G versus others was less common in the pre-eclampsia group (P=0.035+/-0.003), compared with the controls. In conclusion, the polymorphisms of the TNF-alpha gene showed a significant haplotype association with susceptibility to pre-eclampsia in the Finnish population.