Aušra Matulevičienė

Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290‐related phenotypes

Leber Congenital Amaurosis (LCA), the most severe inherited retinal dystrophy, is genetically heterogeneous, with 14 genes accounting for 70% of patients. Here, 91 LCA probands underwent LCA chip analysis and subsequent sequencing of 6 genes (CEP290, CRB1, RPE65, GUCY2D, AIPL1and CRX), revealing mutations in 69% of the cohort, with major involvement of CEP290 (30%). In addition, 11 patients with early‐onset retinal dystrophy (EORD) and 13 patients with Senior‐Loken syndrome (SLS), LCA‐Joubert syndrome (LCA‐JS) or cerebello‐oculo‐renal syndrome (CORS) were included. Exhaustive re‐inspection of the overall phenotypes in our LCA cohort revealed novel insights mainly regarding the CEP290‐related phenotype. The AHI1 gene was screened as a candidate modifier gene in three patients with the same CEP290 genotype but different neurological involvement. Interestingly, a heterozygous novel AHI1 mutation, p.Asn811Lys, was found in the most severely affected patient. Moreover, AHI1 screening in five other patients with CEP290‐related disease and neurological involvement revealed a second novel missense variant, p.His758Pro, in one LCA patient with mild mental retardation and autism. These two AHI1 mutations might thus represent neurological modifiers of CEP290‐related disease.

Replication of Novel Susceptibility Locus for Nonsyndromic Cleft Lip With or Without Cleft Palate on Chromosome 8q24 in Estonian and Lithuanian Patients

Cleft lip with or without cleft palate (CL/P) is one of the mostcommonhumanbirthdefects.CL/Pmayoccuraspartofacomplexmalformation syndrome or, as is more commonly the case, as anonsyndromic malformation. In European populations non-syndromic cleft lip with or without cleft palate (NSCL/P) has abirth prevalence of 1/700–1/1,000. NSCL/P has a multifactorialetiology resulting from interactions between multiple genetic andenvironmentalfactors.Nonsyndromiccleftpalateonly(NSCPO)isthe second most common form of nonsyndromic clefting, with aprevalence of 1/2,000 in most European populations. AlthoughNSCL/P and NSCPO are generally considered to be develop-mentally and genetically distinct entities, there is evidence thatthey may have an etiological overlap [Kondo et al., 2002; Sivertsenet al., 2008].The identification of susceptibility genes for NSCL/P has beenthe subject of extensive research. Of the many candidate genesinvestigated, however, only the IRF6 gene has shown a convincingdegreeofconsistencyacrossstudies[Zuccheroetal.,2004;Rahimovet al., 2008]. The first genome-wide association scan (GWAS)recently reported a new major susceptibility locus at chromosome8q24.21,with the strongestassociationsignal having been observedfor rs987525 (P¼3.34 10

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.

Genetic Variants in COL2A1, COL11A2, and IRF6 Contribute Risk to Nonsyndromic Cleft Palate

BACKGROUND Orofacial clefts are among the most common birth defects with a strong genetic component. Nonsyndromic cleft palate (NSCP) is a complex malformation determined by the interaction between multiple genes and environmental risk factors. METHODS We conducted a case-control association study to investigate the role of 40 candidate genes in predisposition to orofacial clefting. Five hundred ninety-one haplotype tagging single nucleotide polymorphism (tagSNPs) were genotyped in a clefting sample from the Baltic region, composed of 104 patients with nonsyndromic cleft palate and 606 controls from an Estonian, Latvian, and Lithuanian population. RESULTS In case-control comparisons, the minor alleles of IRF6 rs17389541 (p = 5.45 × 10(-4)) and COL2A1 rs1793949 (p = 7.26 × 10(-4)) were associated with increased risk of NSCP. Multiple haplotypes in COL2A1 and COL11A2 and haplotypes in WNT3, FGFR1, and CLPTM1were associated with NSCP. The strongest associations were found for IRF6 haplotype rs17389541/rs9430018 GT (p = 2.23 × 10(-4)) and COL2A1 haplotype rs12822608/rs6823 GC (p = 3.68 × 10(-4)). The strongest epistatic interactions were observed between MSX1 and BMP2, FGF1 and PVRL2, and COL2A1 and FGF2 genes. CONCLUSIONS This study provides for the first time evidence of the implication of IRF6, COL2A1, and WNT3 in the occurrence of NSCP. It is likely that variation in cartilage collagen II and XI genes, IRF6, and the Wnt and FGF signaling pathway genes contributes susceptibility to nonsyndromic cleft palate in Northeastern European populations.

A single gene deletion on 4q28.3: PCDH18--a new candidate gene for intellectual disability?

We report a boy with severe developmental delay, seizures, microcephaly, hypoplastic corpus callosum, internal hydrocephalus and dysmorphic features (narrow forehead, round face, deep-set eyes, blue sclerae, large and prominent ears, nose with anteverted nares, thin upper lip, small and wide-spaced teeth, hyperextensibility of the elbows, wrists, and fingers, fingertip pads, broad hallux, sacral dimple), carrying a 1.53 Mb interstitial deletion at 4q28.3. The deletion was detected by Agilent 105K oligo-array genome hybridization and involves the genomic region between 137,417,338 and 138,947,282 base pairs on chromosome 4 (NCBI build 36). The alteration was inherited from a healthy mother and contains a single gene, PCDH18 which encodes a cadherin-related neuronal receptor thought to play a role in the establishment and function of cell-cell connections in the brain. Thus, haploinsufficiency of this gene may contribute to altered brain development and associated malformations. We found that this deletion is a private inherited copy number variation that is associated with specific clinical findings in our patient and propose the PCDH18 gene as a possible candidate gene for intellectual disability.

NSD1 duplication in Silver-Russell syndrome (SRS): molecular karyotyping in patients with SRS features.

Silver–Russell syndrome (SRS) is a growth retardation syndrome characterized by intrauterine and postnatal growth retardation, relative macrocephaly and protruding forehead, body asymmetry and feeding difficulties. Nearly 50% of cases show a hypomethylation in 11p15.5, in 10% maternal uniparental disomy of chromosome 7 is present. A significant number of patients with SRS features also exhibit chromosomal aberrations. We analyzed 43 individuals referred for SRS genetic testing by molecular karyotyping. Pathogenic variants could be detected in five of them, including a NSD1 duplication in 5q35 and a 14q32 microdeletion. NSD1 deletions are detectable in overgrowth disorders (Sotos syndrome and Beckwith–Wiedemann syndrome), whereas NSD1 duplications are associated with growth retardation. The 14q32 deletion is typically associated with Temple syndrome (TS14), but the identification of a patient in our cohort reflects the clinical overlap between TS14 and SRS. As determination of molecular subtypes is the basis for a directed counseling and therapy, the identification of pathogenic variants in >10% of the total cohort of patients referred for SRS testing and in >16% of characteristic individuals with the characteristic SRS phenotype confirms the need to apply molecular karyotyping in this cohort.

SOX9 p.Lys106Glu mutation causes acampomelic campomelic dysplasia: Prenatal and postnatal clinical findings

Grant sponsor: Lithuanian-Swiss. Correspondence to: Egle Preiksaitiene, M.D., Ph.D., Clinical Geneticist, Department of Human and Medical Genetics, Vilnius University, Santariskiu 2, Vilnius, Lithuania. E-mail: eglepreiksaitiene@gmail.com Article first published online in Wiley Online Library (wileyonlinelibrary.com): 24 November 2015 DOI 10.1002/ajmg.a.37466 How to Cite this Article: Preiksaitiene E, Benu sienė E, Matulevi cienė A, Grigalionienė K, Utkus A, Ku cinskas V. 2016. SOX9 p.Lys106Glu mutation causes acampomelic campomelic dysplasia: Prenatal and postnatal clinical findings.

Opposite chromosome constitutions due to a familial translocation t(1;21)(q43;q22) in 2 cousins with development delay and congenital anomalies: A case report

Rationale: Chromosomal rearrangements are the major cause of multiple congenital abnormalities and intellectual disability. Patient concerns and diagnosis: We report 2 first cousins with unbalanced chromosomal aberrations of chromosomes 1 and 21, resulting from balanced familial translocation. Chromosome microarray analysis revealed 8.5 Mb1q43q44 duplication/21q22.2q22.3 deletion and 6.8 Mb 1q43q44 deletion/21q22.2q22.3 duplication. Among other features, cognitive and motor development delay and craniofacial anomalies are present in both patients, whereas congenital heart defect and hearing impairment is only present in patient carrying 1q43q44 duplication/21q22.2q22.3 deletion. Lessons: In this report, we provide detailed analysis of the phenotypic features of both patients as well as compare our data with previously published reports of similar aberrations and discuss possible functional effects of AKT3, CEP170, ZBTB18, DSCAM, and TMPRSS3 genes included in the deleted and/or duplicated regions. Partial trisomy 1q/monosomy 21q has only been reported once before, and this is the first report of partial monosomy 1q/trisomy 21q. The expressed phenotype of mirroring chromosomal aberrations in our patients supports the previous suggestion that the dosage effect of some of the genes included in deleted/duplicated regions may result in opposite phenotypes of the patients.

Familial Distal Monosomy 5p15.3-pter With Trisomy 12q24.2-qter Resulting in Neurodevelopmental Delay and Dysmorphic Features

Developmental delay and brain anomalies leading to significant morbidity and mortality are frequently caused by chromosomal rearrangements. We report on a familial unbalanced translocation resulting in distal monosomy 5p15.3-pter with trisomy 12q24.2-qter in 2 half siblings with cerebral dysgenesis, severe intellectual disability, dysmorphic features, progressive weakness, and atrophy of muscles.

Genotype and phenotype data analysis and visualization

In this paper, we present a comparative analysis of hierarchical clustering and multidimensional scaling methods for genotype and phenotype data analysis. Fishers exact test was applied to determinate dependencies between congenital anomalies. In order to determine the relationship between the dependences of congenital anomalies, deformations, these systems’ micro anomalies and congenital anomalies associated with orofacial clefs, the Spearman and Kendall correlation coefficients were applied. It has been detected which methods are better for genetic data visualization.