Algirdas Utkus

Variation in FGF1, FOXE1, and TIMP2genes is associated with nonsyndromic cleft lip with or without cleft palate

BACKGROUND Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common complex birth defect caused by the interaction between multiple genes and environmental factors. METHODS Five hundred and eighty-seven single nucleotide polymorphisms in 40 candidate genes related to orofacial clefting were tested for association with CL/P in a clefting sample composed of 300 patients and 606 controls from Estonian, Latvian, and Lithuanian populations. RESULTS In case-control comparisons, the minor alleles of FGF1 rs34010 (p = 4.56 × 10(-4) ), WNT9B rs4968282 (p = 0.0013), and FOXE1 rs7860144 (p = 0.0021) were associated with a decreased risk of CL/P. Multiple haplotypes in FGF1, FOXE1, and TIMP2 and haplotypes in WNT9B, PVRL2, and LHX8 were associated with CL/P. The strongest association was found for protective haplotype rs250092/rs34010 GT in the FGF1 gene (p = 5.01 × 10(-4) ). The strongest epistatic interaction was observed between the COL2A1 and WNT3 genes. CONCLUSIONS Our results provide for the first time evidence implicating FGF1 in the occurrence of CL/P, and support TIMP2 and WNT9B as novel loci predisposing to CL/P. We have also replicated recently reported significant associations between variants in or near FOXE1 and CL/P. It is likely that variation in FOXE1, TIMP2, and the FGF and Wnt signaling pathway genes confers susceptibility to nonsyndromic CL/P in Northeastern European populations.

Two mutations in IFITM5 causing distinct forms of osteogenesis imperfecta

The IFITM5 gene has recently been found to be mutated in patients with autosomal dominant osteogenesis imperfecta (OI) type V. This form of OI is characterized by distinctive clinical manifestations, including hyperplastic callus formation at the site of fractures, calcification of the interosseous membrane of the forearm, and dislocation of the head of the radius. Notably, in spite of the fact that a considerable number of patients with IFITM5 mutations have been identified, to date all of them have been shown to have the same heterozygous mutation (c.‐14C>T). Herein, we describe one patient with a de novo c.119C>T heterozygous mutation in IFITM5, which predicts p.Ser40Leu, and another with the recurrent c.‐14C>T transition that was also apparently de novo. While the patient with the p.Ser40Leu mutation had none of the typical signs of OI type V and was diagnosed with limb shortening at prenatal stages, the patient with the c.‐14C>T mutation developed hyperplastic calluses and had calcification of the forearm interosseous membrane. This study challenges the lack of allelic and clinical heterogeneity in IFITM5 mutations.

A new single gene deletion on 2q34: ERBB4 is associated with intellectual disability.

We report on a 15‐year‐old patient with hyperactivity, intellectual disability and severe speech developmental delay. An array CGH analysis revealed de novo 2q34 deletion, 958 kb in size, involving a single protein coding gene ERBB4 (position 212,505,294–213,463,152; NCBI build 36). The ERBB4 gene is important in numerous neurobiological processes in both the developing and the adult brain. The NRG1–ERBB4 signaling pathway has been recently implicated in the pathophysiology of schizophrenia and epilepsy. Many risk haplotypes were identified in several studies across different populations. The severe clinical consequences in our patient demonstrate that the haploinsufficiency of ERBB4 is crucial for intellectual and cognitive function. These observations are compatible with previously reported results.

Thiamine responsive megaloblastic anemia syndrome: A novel homozygous SLC19A2 gene mutation identified

Thiamine responsive megaloblastic anemia syndrome (TRMAS) is a rare autosomal recessive disorder especially in countries where consanguinity is uncommon. Three main features are characteristic of the disease – megaloblastic anemia, early onset deafness, and non‐type I diabetes. TRMAS is a Mendelian disorder; a gene SLC19A2 coding high affinity thiamine transporter mediating vitamin B1 uptake through cell membrane has been identified. We present the first patient with TRMAS in Lithuania – a 3‐year‐old boy born to a non‐consanguineous family with a novel homozygous SLC19A2 gene mutation. The patient had insulin dependent diabetes (onset 11 months), respiratory illness (onset 11 months), bilateral profound hearing loss (onset at 7 months, verified at 20 months), refractory anemia (onset 2 years), and decreased vision acuity and photophobia (onset 2.5 years). The psychomotor abilities developed according to age. Phenotypic evaluation did not reveal any dysmorphic features. The clinical diagnosis of TRMAS was suspected and daily supplementation with thiamine 100 mg was started. The condition of the patient markedly improved several days after the initiation of treatment. The results of SLC19A2 gene molecular testing confirmed the clinical diagnosis – novel homozygous c.[205G>T], p.[(Val69Phe)] mutation changing conserved amino acid residue or even interfering the mRNA splicing. Clinical heterogeneity, diverse dynamics, and wide spectrum of symptoms are aggravating factors in the diagnosis. The possibility of treatment demands early recognition of disorder to facilitate the improvement of the patients condition.

A 72-year-old danish puzzle resolved : Comparative analysis of phenotypes in families with different-sized HOXD13 polyalanine expansions

A phenotype–genotype correlation was previously described for carriers of different sized of polyalanine expansions in HOXD13. We report on a detailed comparison of 55 members (∼220 limbs) from 4 Danish families with duplications of 21 or 27 bp, expanding the polyalanine repeat from 15 to 22 and 24 residues, respectively. Two of these were previously described by Danish pioneers of human genetics, Tage Kemp and Oluf Thomsen. A clinical score was assigned to each limb based on manifestations assumed to represent different degrees of a duplication defect in hand rays 3–4 and foot rays 4–5. The length of metacarpals and phalangeal bones in rays 1, 2, and 5 was measured on hand radiographs and converted to Z‐scores. The relative difference between corresponding right and left bones and directional, total, and fluctuating asymmetry was calculated for each individual. All of these parameters were compared between carriers of the +9 alanine expansion, the +7 alanine expansion, and non‐mutation carriers with affected parents from the two families. Upper limb scores and the rate of abnormal bones (>2SD) were significantly higher in the first group than in the others. The first metacarpal and the middle phalanx of the little finger were significantly shorter, and the proximal phalanx of the index finger was significantly longer in this group than in the others. An increased level of total and fluctuating asymmetry was observed in long expansion carriers. Thus, our data have added evidence to the phenotype–genotype correlation previously reported, which was further extended to include lesser involvement of bones in ray 1, 2, and 5.

A novel de novo 1.8 Mb microdeletion of 17q21.33 associated with intellectual disability and dysmorphic features

We report on a de novo 17q21.33 microdeletion, 1.8 Mb in size, detected in a patient with mild intellectual disability, growth retardation, poor weight gain, microcephaly, long face, large beaked nose, thick lower lip, micrognathia and other dysmorphic features. The deletion was detected by whole-genome genotyping BeadChip assay and involves the genomic region between 45,682,246 and 47,544,816 bp on chromosome 17. Among the 24 RefSeq genes included in this deletion are the CA10 and CACNA1G genes that are involved in brain development and neurological processes. A possible candidate gene for the prenatal and postnatal growth retardation is the CHAD gene, which product chondroadherin is a cartilage protein with cell binding properties. These three genes may be responsible for the patients phenotype.

AMPD1 rs17602729 is associated with physical performance of sprint and power in elite Lithuanian athletes

BackgroundThe C34T genetic polymorphism (rs17602729) in the AMPD1 gene, encoding the skeletal muscle-specific isoform of adenosine monophosphate deaminase (AMPD1), is a common polymorphism among Caucasians that can impair exercise capacity. The aim of the present study was twofold: (1) to determine the C34T AMPD1 allele/genotype frequency distributions in Lithuanian athletes (n = 204, stratified into three groups: endurance, sprint/power and mixed) and compare them with the allele/genotype frequency distributions in randomly selected healthy Lithuanian non-athletes (n = 260) and (2) to compare common anthropometric measurements and physical performance phenotypes between the three groups of athletes depending on their AMPD1 genotype.ResultsThe results of our study indicate that the frequency of the AMPD1 TT genotype was 2.4% in the control group, while it was absent in the athlete group. There were significantly more sprint/power-orientated athletes with the CC genotype (86.3%) compared with the endurance-orientated athletes (72.9%), mixed athletes (67.1%), and controls (74.2%). We determined that the AMPD1 C34T polymorphism is not associated with aerobic muscle performance phenotype (VO2max). For CC genotype the short-term explosive muscle power value (based on Vertical Jump test) of athletes from the sprint/power group was significantly higher than that of the endurance group athletes (P < 0.05). The AMPD1 CC genotype is associated with anaerobic performance (Vertical Jump).ConclusionsThe AMPD1 C allele may help athletes to attain elite status in sprint/power-oriented sports, and the T allele is a factor unfavourable for athletics in sprint/power-oriented sports categories. Hence, the AMPD1 C allele can be regarded as a marker associated with the physical performance of sprint and power. Replications studies are required to confirm this association.

Few associations of candidate genes with nonsyndromic orofacial clefts in the population of Lithuania.

Nonsyndromic orofacial clefting (NS-OFC) is a common complex multifactorial trait with a considerable genetic component and a number of candidate genes suggested by various approaches. Twenty biallelic and microsatellite DNA markers in the strong candidate lociTGFA, TGFB3, GABRB3, RARA, andBCL3 were analysed for allelic association with the NS-OFC phenotype in 112 nuclear families (proband + both parents) from Lithuania by using the transmission disequilibrium test (TDT). Associations were found between theTGFA gene marker rs2166975 and nonsyndromic cleft palate only (CPO) phenotype (P = 0.045, df 1) as well as between the D2S292 marker and the cleft lip with or without cleft palate (CL/CP) phenotype in allele-wise TDT (P = 0.005, df 9) and genotype-wise TDT (P = 0.021, df 24). A weak association (P = 0.085, df 3) of the BCL3 marker (BCL3 gene) with the risk of CPO was also found. Thus our initial results support the contribution of allelic variation in theTGFA locus to the aetiology of CL/CP in the population of Lithuania but they do not point toTGFA as a major causal gene. Different roles of theTGFA andBCL3 genes in the susceptibility to NS-OFC phenotypes are suggested.

Considering specific clinical features as evidence of pathogenic copy number variants

Since the introduction of high-resolution microarray technologies, it has become apparent that structural chromosomal rearrangements can lead to a wide variety of clinical manifestations, including developmental delay/intellectual disability (DD/ID). It has been shown previously that the diagnostic yield of genome-wide array-based identification of submicroscopic alterations in patients with ID varies widely and depends on the patient selection criteria. More attempts have recently been made to define the phenotypic clues of pathogenic copy number variants (CNVs). The aim of this study was to investigate a well-phenotyped cohort of patients with DD/ID and determine whether certain clinical features may serve as indicators for pathogenic CNVs. A retrospective analysis was conducted for patients with DD/ID (n = 211) who were tested using genome-wide chromosomal microarray technologies and a review of the clinical data was performed. Pathogenic CNVs were detected in 29 patients. In comparison with individuals who had normal molecular karyotyping results (n = 182), malformations of the musculoskeletal system; congenital malformations of the CNS (particularly hydrocephalus and congenital malformations of the corpus callosum); minor anomalies of the eye, face, and neck subgroup (particularly downward-slanting palpebral fissures, minor anomalies of the ear, and micrognathia); brachydactyly; and umbilical hernia were more common in patients with chromosomal alterations. A multivariate logistic regression analysis allowed the identification of three independent pathogenic CNV predictors: congenital malformations of the corpus callosum, minor anomalies of the ear, and brachydactyly. Insights into the chromosomal phenotype may help to increase the diagnostic yield of microarray technologies and sharpen the distinction between chromosomal alterations and other conditions.

Duplication of segment 1p21 following paternal insertional translocation, ins(6;1)(q25;p13.3p22.1).

A moderately mentally retarded 3 year old boy showed minor anomalies including a prominent forehead and flat occiput, exophthalmos, large and prominent ears, high arched palate, umbilical hernia, sacral dimple, and irregular position of the toes. Cardiac sonography disclosed a chorda running through the left ventricle. Cytogenetic investigation of the family showed a balanced insertional translocation of segment 1p13→p22 into distal 6q in the father which had led, through unbalanced segregation, to duplication of 1p13.3→p22.1 in the proband. Familial duplication of such a small interstitial segment of 1p has not been reported previously, and the paucity of abnormal physical findings in the proband compared to previous patients with a similar aberration is remarkable.