NullHap – a versatile application to estimate haplotype frequencies from unphased genotypes in the presence of null alleles

<p>Abstract</p> <p>Background</p> <p>Laboratory techniques used to determine haplotypes are often too expensive for large-scale studies and lack of phase information is commonly overcome using likelihood-based calculations. Whereas a number of programs are available for that purpose, none of them can handle loci with both multiple and null alleles.</p> <p>Results</p> <p>Here we present a description of a modified Expectation – Maximization algorithm as well as its implementation (NullHap) which allow to effectively overcome these limitations. As an example of application we used Nullhap to reanalyze published data on distribution of <it>KIR </it>genotypes in Polish psoriasis patients and controls showing that the <it>KIR2DS4/1D </it>locus may be a marker of <it>KIR2DS1 </it>haplotypes with different effects on disease susceptibility.</p> <p>Conclusion</p> <p>The developed application can estimate haplotype frequencies for every type of polymorphism and can effectively be used in genetic research as illustrated by a novel finding regarding the genetic susceptibility to psoriasis.</p

The Genetic Basis of Graves' Disease

The presented comprehensive review of current knowledge about genetic factors predisposing to Graves’ disease (GD) put emphasis on functional significance of observed associations. In particular, we discuss recent efforts aimed at refining diseases associations found within the HLA complex and implicating HLA class I as well as HLA-DPB1 loci. We summarize data regarding non-HLA genes such as PTPN22, CTLA4, CD40, TSHR and TG which have been extensively studied in respect to their role in GD. We review recent findings implicating variants of FCRL3 (gene for FC receptor-like-3 protein), SCGB3A2 (gene for secretory uteroglobin-related protein 1- UGRP1) as well as other unverified possible candidate genes for GD selected through their documented association with type 1 diabetes mellitus: Tenr–IL2–IL21, CAPSL (encoding calcyphosine-like protein), IFIH1(gene for interferon-induced helicase C domain 1), AFF3, CD226 and PTPN2. We also review reports on association of skewed X chromosome inactivation and fetal microchimerism with GD. Finally we discuss issues of genotype-phenotype correlations in GD

Lamin A/C mutations in dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure and heart transplant. Mutations in 60 genes have been associated with DCM. Approximately 6% of all DCM cases are caused by mutations in the lamin A/C gene (LMNA). LMNA codes for type-V intermediate filaments that support the structure of the nuclear membrane and are involved in chromatin structure and gene expression. Most LMNA mutations result in striated muscle diseases while the rest affects the adipose tissue, peripheral nervous system, multiple tissues or lead to progeroid syndromes/overlapping syndromes. Patients with LMNA mutations exhibit a variety of cellular and physiological phenotypes. This paper explores the current phenotypes observed in LMNA-caused DCM, the results and implications of the cellular and animal models of DCM and the prevailing theories on the pathogenesis of laminopathies.

Risk factors of diabetic foot of neuropathic origin in patients with type 2 diabetes

Wstęp: Zespół stopy cukrzycowej jest powikłaniem cukrzycy prowadzącym do powstania nawracających owrzodzeń, ryzyka zapalenia kości i szpiku kostnego, a ostatecznie martwicy tkanek wymagającej amputacji kończyny dolnej. Zespół stopy cukrzycowej o etiologii neuropatycznej jest najczęstszym rodzajem tego powikłania, w którym dominują objawy neuropatii autonomicznej i czuciowo-ruchowej. Celem pracy była ocena czynników ryzyka neuropatycznego zespołu stopy cukrzycowej u chorych z cukrzycą typu 2. Materiał i metody: Do badania włączono 240 osób, 74 chorych z zespołem stopy cukrzycowej typu neuropatycznego oraz 166 chorych z cukrzycą typu 2 bez zespołu stopy cukrzycowej. Grupę badaną i kontrolną dobrano pod względem struktury wieku. Chorych z chorobą naczyń obwodowych wyłączono z badania. Badanie przeprowadzono w Katedrze i Klinice Gastroenterologii i Chorób Przemiany Materii Warszawskiego Uniwersytetu Medycznego. Użyto modelu regresji logistycznej oraz testów: χ2, U Mann-Whitneya i t-Studenta. Wyniki: Analiza regresji logistycznej wykazała, że czynnikami ryzyka neuropatycznego zespołu stopy cukrzycowej były płeć męska (OR = 6,63; 95% CI: 3,31–13,27; p = 0,00001), czas trwania cukrzycy (OR = 1,10; 95% CI: 1,06–1,14; p = 0,00001), wzrost (OR = 1,09; 95% CI: 1,06–1,13; p = 0,00001), masa ciała (OR = 1,04; 95% CI: 1,04–1,06; p = 0,00001) i obwód talii (OR = 1,05; 95% CI: 1,02–1,08; p = 0,001). Zaobserwowano również korelację między neuropatycznym zespołem stopy cukrzycowej a wartością BMI, która nie miała wpływu na ryzyko wystąpienia zespołu stopy cukrzycowej (p = 0,01). Wnioski: Istnienie specyficznych czynników zwiększających ryzyko wystąpienia neuropatycznego zespołu stopy cukrzycowej może się przyczynić do wyłonienie grupy chorych, którzy mogliby odnieść największą korzyść z objęcia długoterminową opieką w warunkach specjalistycznej opieki zdrowotnej. Wczesna identyfikacja takich chorych może zmniejszyć ryzyko wielomiesięcznego gojenia owrzodzeń, a także amputacji kończyn dolnych.Introduction: Diabetic foot is a diabetes mellitus complication leading to recurrent ulcerations, risk of osteomyelitis and tissue necrosis which may finally result in amputation. Diabetic foot of neuropathic origin manifesting as autonomic and sensory motor neuropathy is the most common type of this complication. The aim of this study was to identify risk factors of diabetic foot of neuropathic origin occurrence in patients with type 2 diabetes. Material and methods: The study included 240 patients, 74 with diabetic foot of neuropathic origin and 166 with diabetes. Cases and controls were matched in terms of age structure. Patients with peripheral arterial disease were excluded from the study. The study was conducted in the Gastroenterology and Metabolic Diseases Department, Medical University of Warsaw, Poland. We used logistic regression models, χ2, U Mann-Whitney’s and t-Student tests. Results: Logistic regression analysis showed that diabetic foot of neuropathic origin risk factors were: male gender (OR = 6.63; 95% CI: 3.31–13.27; p = 0.00001), duration of diabetes (OR = 1.10; 95% CI: 1.06–1.14; p = 0.00001), height (OR = 1.09; 95% CI: 1.06–1.13; p = 0.00001), weight (OR = 1.04; 95% CI: 1.04–1.06; p = 0.00001) and waist circumference (OR = 1.05; 95% CI: 1.02–1.08; p = 0.001). Although there was a correlation between diabetic foot of neuropathic origin and BMI value, it had no impact on DF occurrence risk. Conclusion: It is possible to identify patients at risk of diabetic foot development by evaluating anthropometric features. The existence of specific factors increasing the odds of diabetic foot of neuropathic origin occurring may lead to the identification of patients at risk of its development

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) – A Polish family with novel SACS mutations

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare hereditary ataxia, characterized by the triad of early-onset cerebellar ataxia, peripheral sensorimotor neuropathy and lower limb spasticity. Although ARSACS is increasingly reported worldwide, we present the first Polish family with a comprehensive clinical and neuropsychological assessment, harboring two novel mutations in the SACS gene. Our results demonstrate the variability in cognitive and behavioral profiles in ARSACS, which is in line with other heredodegenerative ataxias. One should be aware of ARSACS in cases of autosomally recessive inherited ataxias without common mutations

An association between genetic variation in the glutamatergic system and suicide attempts in alcoholâ dependent individuals

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138265/1/ajad12571_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138265/2/ajad12571.pd

Case Report: Adenosine kinase deficiency diagnosed 10 years after liver transplantation: Novel phenotypic insights

Adenosine kinase (ADK) deficiency is a rare inborn error of methionine and adenosine metabolism. So far, a total of 27 patients with ADK deficiency have been reported. Here, we describe the first Polish patient diagnosed with ADK deficiency, aiming to highlight the clinical presentation of disease, emphasize diagnostic difficulties, and report the long-term follow-up. Six-month-old patient presented with cholestatic liver disease, macrocytic anemia, developmental delay, generalized hypotonia, delayed brain myelination, and elevated levels of serum methionine. A decrease of mitochondrial respiratory chain complex II and III activity were found in the postnuclear supernatants obtained from skeletal muscle biopsy. The patient underwent living-donor liver transplantation (LTx) at 14 months of age. Ten-year follow-up after LTx revealed a preserved good liver function, persistent regenerative macrocytic anemia, progressive neurological disease but disappearance of brain MR changes, short stature, and cortisol deficiency. Whole exome sequencing revealed the patient to be affected with two novel ADK variants, which pathogenicity was confirmed biochemically by demonstration of elevated concentration of S-adenosylhomocysteine