BackgroundCongenital anomalies (CAs) increase the risk of death during infancy and childhood. Thi... more BackgroundCongenital anomalies (CAs) increase the risk of death during infancy and childhood. This study aimed to evaluate the accuracy of using death certificates to estimate the burden of CAs on mortality for children under 10 years old.MethodsChildren born alive with a major CA between 1 January 1995 and 31 December 2014, from 13 population-based European CA registries were linked to mortality records up to their 10th birthday or 31 December 2015, whichever was earlier.ResultsIn total 4199 neonatal, 2100 postneonatal and 1087 deaths in children aged 1–9 years were reported. The underlying cause of death was a CA in 71% (95% CI 64% to 78%) of neonatal and 68% (95% CI 61% to 74%) of postneonatal infant deaths. For neonatal deaths the proportions varied by registry from 45% to 89% and by anomaly from 53% for Down syndrome to 94% for tetralogy of Fallot. In children aged 1–9, 49% (95% CI 42% to 57%) were attributed to a CA. Comparing mortality in children with anomalies to population...
BackgroundYounger mothers are at a greater risk of having a pregnancy with gastroschisis and the ... more BackgroundYounger mothers are at a greater risk of having a pregnancy with gastroschisis and the risk is higher in the United Kingdom than other European countries. Gastroschisis is thought to be a vascular disruption anomaly and the aim of this study was to analyze the prevalence of other possible vascular disruption anomalies to determine whether both the younger maternal age and the UK associations also occur with these anomalies.MethodsAll pregnancies with anomalies considered potentially due to vascular disruption from January 1, 2005 to December 31, 2017 from 26 European population‐based congenital anomaly registries who were members of EUROCAT were analyzed. Multilevel models were used to allow for differences between registries when analyzing associations with maternal age, year of birth and whether the registry was in the United Kingdom.ResultsThere were 5,220 cases with potential vascular disruption anomalies, excluding chromosomal and genetic conditions, with a prevalence...
Osteogenesis imperfecta (OI) is a phenotypically and molecularly heterogeneous group of heritable... more Osteogenesis imperfecta (OI) is a phenotypically and molecularly heterogeneous group of heritable connective tissue disorders characterized by low bone mineral density, recurrent fractures, and bone deformities. Most cases of OI are inherited in an autosomal dominant manner and are caused by mutations in the COL1A1 and COL1A2 genes, leading to quantitative or qualitative defects in type 1 collagen. More recently, a number of other genes responsible for both recessive and dominant forms of this condition have been identifi ed. In this brief review, we discuss current understanding of clinical assessment, follow-up and pharmacological therapies for the treatment of OI. The multidisciplinary surveillance in patients with OI includes periodical hearing and vision testing, dental examination, spirometry or body plethysmography, evaluation of heart/valvular function, and neurological and psychological assessment. There is a need for regular assessment of bone mineral density (BMD) to eval...
Cells from people with Down syndrome (DS) show faster accumulation of DNA damage and epigenetic a... more Cells from people with Down syndrome (DS) show faster accumulation of DNA damage and epigenetic aging marks. Causative mechanisms remain un-proven and hypotheses range from amplified chromosomal instability to actions of several supernumerary chromosome 21 genes. Plasma immunoglobulin G (IgG) glycosylation profiles are established as a reliable predictor of biological and chronological aging. We performed IgG glycan profiling of n=246 individuals with DS (208 adults and 38 children) from three European populations and compared these to age-, sex- and demography-matched general populations. We uncovered very significantly increased IgG glycosylation aging marks associated with DS. Average levels of IgG glycans without galactose (G0) and those with two galactoses (G2) as a function of age in persons with DS corresponded to levels detected in 19 years older euploid individuals. Some aging marks were significant already in children with DS. Remarkably, the IgG glycan profiles of a child...
Background: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by defe... more Background: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by defects in genes coding for different lysosomal enzymes which degrade glycosaminoglycans. Impaired lysosomal degradation causes cell dysfunction leading to progressive multiorgan involvement, disabling consequences and poor life expectancy. Enzyme replacement therapy (ERT) is now available for most MPS types, offering beneficial effects on disease progression and improving quality of life of patients. The landscape of MPS in Europe is not completely described and studies on availability of treatment show that ERT is not adequately implemented, particularly in Southern and Eastern Europe. In this study we performed a survey analysis in main specialist centers in Southern and Eastern European countries, to outline the landscape of disease management in the region and understand ERT implementation, with particular reference to MPS IVA.Results: 19 experts from 14 Southern and Eastern European co...
Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia,... more Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced...
AimTo determine the diagnostic yield and criteria that could help to classify and interpret the c... more AimTo determine the diagnostic yield and criteria that could help to classify and interpret the copy number variations (CNVs) detected by chromosomal microarray (CMA) technique in patients with congenital and developmental abnormalities including dysmorphia, developmental delay (DD) or intellectual disability (ID), autism spectrum disorders (ASD) and congenital anomalies (CA).MethodCMA analysis was performed in 337 patients with DD/ID with or without dysmorphism, ASD, and/or CA. In 30 of 337 patients, chromosomal imbalances had previously been detected by classical cytogenetic and molecular cytogenetic methods.ResultsIn 73 of 337 patients, clinically relevant variants were detected and better characterized. Most of them were >1 Mb. Variants of unknown clinical significance (VOUS) were discovered in 35 patients. The most common VOUS size category was <300 kb (40.5%). Deletions and de novo imbalances were more frequent in pathogenic CNV than in VOUS category. CMA had a high diagnostic yield of 43/307, excluding patients previously detected by other methods.ConclusionCMA was valuable in establishing the diagnosis in a high proportion of patients. Criteria for classification and interpretation of CNVs include CNV size and type, mode of inheritance, and genotype-phenotype correlation. Agilent ISCA v2 Human Genome 8x60 K oligonucleotide microarray format proved to be reasonable resolution for clinical use, particularly in the regions that are recommended by the International Standard Cytogenomic Array (ISCA) Consortium and associated with well-established syndromes.
Resulting from several basic scientific disciplines, genetics has made impressive progress in the... more Resulting from several basic scientific disciplines, genetics has made impressive progress in the last century by discoveries of the heredity rules and genome structure, and by identification of the genes that determine the occurrence and characteristics of human diseases. In Croatia, the development of genetics began in the middle of the past century by the pioneering work of clinicians and basic scientists, which resulted in significant development of this scientific discipline that has quickly found its practical application in clinical genetics-cytogenetics, molecular genetics and prenatal diagnosis. The rapid advancement of technology and knowledge of genetics in recent decades has led to the development of genomics and related disciplines, entering the revolutionary new era of personalized medicine. Currently, much more data can be collected than interpreted. The data of electronic medical records, genomics, epigenetics, proteomics, meta- bolomics and microbiomics should be in...
Osteogenesis imperfecta or brittle bone disease, a heritable disorder of connective tissue, is th... more Osteogenesis imperfecta or brittle bone disease, a heritable disorder of connective tissue, is the most common of the inherited disorders primarily affecting bone. There are approximately 400 individuals with OI in Croatia alone. It is estimated that twice that number is present, represented by individuals with mild OI in whom the diagnosis has not been made. Due to the relatively low number of patients in the general population, treating physicians have limited experience with this disease, either with children or adults. The basis of this disease in European populations is mostly the result of defects in the structure or processing of collagen type I, an important protein of the extracellular matrix of many tissues. Presently, molecular defects in 16 different genes have been discovered to result in at least one type of OI of which 14 are not COL1 mutation loci. Although fractures occurring with no injury or minor injury are the hallmark of OI, other non-mineralized tissues can be...
The aim of this study was to determine whether deletion 22q11.2 studies should become apart of a ... more The aim of this study was to determine whether deletion 22q11.2 studies should become apart of a standardized diagnostic workup for selected groups of at risk patients. We prospectively investigated four cohorts of unselected patients referred because of 1) congenital heart defect (CHD), 2) palatal anomalies, 3) hypocalcaemia, 4) dysmorphic features suggestive of del 22q11.2. Fluorescence in situ hybridization analysis revealed deletion 22q11.2 in 9.4% (6/64) patients with CHD. From 18 patients referred because of the hypocalcaemia, six (33.3%) had 22q11.2 deletion. In the group of 31 children with dysmorphic traits, the diagnosis was confirmed in two (6.4%) patients. None of the 58 children with palatal anomalies showed evidence of 22q11.2 deletion. Testing for the 22q11.2 microdeletion can be recommended in all patients with conotruncal heart defects and in patients with hypocalcaemia. It should be also considered in patients presenting only with dysmorphic traits suggestive of de...
Combined cytogenetic, fluorescence in situ hybridization (FISH), and molecular analysis are usefu... more Combined cytogenetic, fluorescence in situ hybridization (FISH), and molecular analysis are useful in the diagnosis of sex chromosome aberrations. These methods were used in karyotype analysis of a 4-year-old girl with mild dysmorphism and growth retardation. Standard cytogenetic and FISH analysis was done on slides obtained from peripheral blood lymphocyte culture, and the molecular study was performed by using DNA polymorphism analysis. Both parents had normal karyotypes. Chromosome analysis of the proband identified the karyotype with 46 chromosomes and a late replicating dicentric X. Interphase FISH with an alpha satellite X centromere probe revealed two mosaic cell lines. Three signals were observed at 84.5% and one signal at 15.5% of the interphase cells. Molecular analysis showed that the dicentric X chromosome was of paternal origin. Based on this study, we concluded that the karyotype of the patient was 45,X/46,X, psu idic(X)(q22.3), with the trisomy Xpter-->q22.3 and mo...
Osteogenesis imperfecta (OI), or brittle bone disease, is a heritable disorder characterized by i... more Osteogenesis imperfecta (OI), or brittle bone disease, is a heritable disorder characterized by increased bone fragility. Four different types of the disease are commonly distinguished, ranging from a mild condition (type I) to a lethal one (type II). Types III and IV are the severe forms surviving the neonatal period. In most cases, there is a reduction in the production of normal type I collagen or the synthesis of abnormal collagen as a result of mutations in the type I collagen genes. These classic forms of OI are described in this review. There are instances, however, where alterations in bone matrix components, other than type I collagen, are the basic abnormalities of the OI. Recently, three such discrete types have been identified by histomorphometric evaluation (types V and VI) and linkage analysis (Rhizomelic OI). They provide evidence for the as yet poorly understood complexity of the phenotype-genotype correlation in OI. We also discuss bisphosphonates treatment as well ...
Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common cause of congenital adrena... more Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common cause of congenital adrenal hyperplasia. Mutations in theCYP11B1gene, which encodes steroid 11β-hydroxylase, are responsible for this autosomal recessive disorder. Here, we describe the molecular genetics of two previously reported male siblings in whom diagnosis of 11β-OHD has been established based on their hormonal profiles displaying high levels of 11-deoxycortisol and hyperandrogenism. Both patients are compound heterozygous for a novel p.E67fs (c.199delG) mutation in exon 1 and a p.R448H (c.1343G>A) mutation in exon 8. We also report the biochemical and molecular genetics data of one new 11β-OHD patient. Sequencing of theCYP11B1gene reveals that this patient is compound heterozygous for a novel, previously undescribed p.R141Q (c.422G>A) mutation in exon 3 and a p.T318R (c.953C>G) mutation in exon 5. All three patients are of Croatian (Slavic) origin and there is no self-reported consanguinity in th...
BackgroundCongenital anomalies (CAs) increase the risk of death during infancy and childhood. Thi... more BackgroundCongenital anomalies (CAs) increase the risk of death during infancy and childhood. This study aimed to evaluate the accuracy of using death certificates to estimate the burden of CAs on mortality for children under 10 years old.MethodsChildren born alive with a major CA between 1 January 1995 and 31 December 2014, from 13 population-based European CA registries were linked to mortality records up to their 10th birthday or 31 December 2015, whichever was earlier.ResultsIn total 4199 neonatal, 2100 postneonatal and 1087 deaths in children aged 1–9 years were reported. The underlying cause of death was a CA in 71% (95% CI 64% to 78%) of neonatal and 68% (95% CI 61% to 74%) of postneonatal infant deaths. For neonatal deaths the proportions varied by registry from 45% to 89% and by anomaly from 53% for Down syndrome to 94% for tetralogy of Fallot. In children aged 1–9, 49% (95% CI 42% to 57%) were attributed to a CA. Comparing mortality in children with anomalies to population...
BackgroundYounger mothers are at a greater risk of having a pregnancy with gastroschisis and the ... more BackgroundYounger mothers are at a greater risk of having a pregnancy with gastroschisis and the risk is higher in the United Kingdom than other European countries. Gastroschisis is thought to be a vascular disruption anomaly and the aim of this study was to analyze the prevalence of other possible vascular disruption anomalies to determine whether both the younger maternal age and the UK associations also occur with these anomalies.MethodsAll pregnancies with anomalies considered potentially due to vascular disruption from January 1, 2005 to December 31, 2017 from 26 European population‐based congenital anomaly registries who were members of EUROCAT were analyzed. Multilevel models were used to allow for differences between registries when analyzing associations with maternal age, year of birth and whether the registry was in the United Kingdom.ResultsThere were 5,220 cases with potential vascular disruption anomalies, excluding chromosomal and genetic conditions, with a prevalence...
Osteogenesis imperfecta (OI) is a phenotypically and molecularly heterogeneous group of heritable... more Osteogenesis imperfecta (OI) is a phenotypically and molecularly heterogeneous group of heritable connective tissue disorders characterized by low bone mineral density, recurrent fractures, and bone deformities. Most cases of OI are inherited in an autosomal dominant manner and are caused by mutations in the COL1A1 and COL1A2 genes, leading to quantitative or qualitative defects in type 1 collagen. More recently, a number of other genes responsible for both recessive and dominant forms of this condition have been identifi ed. In this brief review, we discuss current understanding of clinical assessment, follow-up and pharmacological therapies for the treatment of OI. The multidisciplinary surveillance in patients with OI includes periodical hearing and vision testing, dental examination, spirometry or body plethysmography, evaluation of heart/valvular function, and neurological and psychological assessment. There is a need for regular assessment of bone mineral density (BMD) to eval...
Cells from people with Down syndrome (DS) show faster accumulation of DNA damage and epigenetic a... more Cells from people with Down syndrome (DS) show faster accumulation of DNA damage and epigenetic aging marks. Causative mechanisms remain un-proven and hypotheses range from amplified chromosomal instability to actions of several supernumerary chromosome 21 genes. Plasma immunoglobulin G (IgG) glycosylation profiles are established as a reliable predictor of biological and chronological aging. We performed IgG glycan profiling of n=246 individuals with DS (208 adults and 38 children) from three European populations and compared these to age-, sex- and demography-matched general populations. We uncovered very significantly increased IgG glycosylation aging marks associated with DS. Average levels of IgG glycans without galactose (G0) and those with two galactoses (G2) as a function of age in persons with DS corresponded to levels detected in 19 years older euploid individuals. Some aging marks were significant already in children with DS. Remarkably, the IgG glycan profiles of a child...
Background: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by defe... more Background: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by defects in genes coding for different lysosomal enzymes which degrade glycosaminoglycans. Impaired lysosomal degradation causes cell dysfunction leading to progressive multiorgan involvement, disabling consequences and poor life expectancy. Enzyme replacement therapy (ERT) is now available for most MPS types, offering beneficial effects on disease progression and improving quality of life of patients. The landscape of MPS in Europe is not completely described and studies on availability of treatment show that ERT is not adequately implemented, particularly in Southern and Eastern Europe. In this study we performed a survey analysis in main specialist centers in Southern and Eastern European countries, to outline the landscape of disease management in the region and understand ERT implementation, with particular reference to MPS IVA.Results: 19 experts from 14 Southern and Eastern European co...
Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia,... more Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced...
AimTo determine the diagnostic yield and criteria that could help to classify and interpret the c... more AimTo determine the diagnostic yield and criteria that could help to classify and interpret the copy number variations (CNVs) detected by chromosomal microarray (CMA) technique in patients with congenital and developmental abnormalities including dysmorphia, developmental delay (DD) or intellectual disability (ID), autism spectrum disorders (ASD) and congenital anomalies (CA).MethodCMA analysis was performed in 337 patients with DD/ID with or without dysmorphism, ASD, and/or CA. In 30 of 337 patients, chromosomal imbalances had previously been detected by classical cytogenetic and molecular cytogenetic methods.ResultsIn 73 of 337 patients, clinically relevant variants were detected and better characterized. Most of them were >1 Mb. Variants of unknown clinical significance (VOUS) were discovered in 35 patients. The most common VOUS size category was <300 kb (40.5%). Deletions and de novo imbalances were more frequent in pathogenic CNV than in VOUS category. CMA had a high diagnostic yield of 43/307, excluding patients previously detected by other methods.ConclusionCMA was valuable in establishing the diagnosis in a high proportion of patients. Criteria for classification and interpretation of CNVs include CNV size and type, mode of inheritance, and genotype-phenotype correlation. Agilent ISCA v2 Human Genome 8x60 K oligonucleotide microarray format proved to be reasonable resolution for clinical use, particularly in the regions that are recommended by the International Standard Cytogenomic Array (ISCA) Consortium and associated with well-established syndromes.
Resulting from several basic scientific disciplines, genetics has made impressive progress in the... more Resulting from several basic scientific disciplines, genetics has made impressive progress in the last century by discoveries of the heredity rules and genome structure, and by identification of the genes that determine the occurrence and characteristics of human diseases. In Croatia, the development of genetics began in the middle of the past century by the pioneering work of clinicians and basic scientists, which resulted in significant development of this scientific discipline that has quickly found its practical application in clinical genetics-cytogenetics, molecular genetics and prenatal diagnosis. The rapid advancement of technology and knowledge of genetics in recent decades has led to the development of genomics and related disciplines, entering the revolutionary new era of personalized medicine. Currently, much more data can be collected than interpreted. The data of electronic medical records, genomics, epigenetics, proteomics, meta- bolomics and microbiomics should be in...
Osteogenesis imperfecta or brittle bone disease, a heritable disorder of connective tissue, is th... more Osteogenesis imperfecta or brittle bone disease, a heritable disorder of connective tissue, is the most common of the inherited disorders primarily affecting bone. There are approximately 400 individuals with OI in Croatia alone. It is estimated that twice that number is present, represented by individuals with mild OI in whom the diagnosis has not been made. Due to the relatively low number of patients in the general population, treating physicians have limited experience with this disease, either with children or adults. The basis of this disease in European populations is mostly the result of defects in the structure or processing of collagen type I, an important protein of the extracellular matrix of many tissues. Presently, molecular defects in 16 different genes have been discovered to result in at least one type of OI of which 14 are not COL1 mutation loci. Although fractures occurring with no injury or minor injury are the hallmark of OI, other non-mineralized tissues can be...
The aim of this study was to determine whether deletion 22q11.2 studies should become apart of a ... more The aim of this study was to determine whether deletion 22q11.2 studies should become apart of a standardized diagnostic workup for selected groups of at risk patients. We prospectively investigated four cohorts of unselected patients referred because of 1) congenital heart defect (CHD), 2) palatal anomalies, 3) hypocalcaemia, 4) dysmorphic features suggestive of del 22q11.2. Fluorescence in situ hybridization analysis revealed deletion 22q11.2 in 9.4% (6/64) patients with CHD. From 18 patients referred because of the hypocalcaemia, six (33.3%) had 22q11.2 deletion. In the group of 31 children with dysmorphic traits, the diagnosis was confirmed in two (6.4%) patients. None of the 58 children with palatal anomalies showed evidence of 22q11.2 deletion. Testing for the 22q11.2 microdeletion can be recommended in all patients with conotruncal heart defects and in patients with hypocalcaemia. It should be also considered in patients presenting only with dysmorphic traits suggestive of de...
Combined cytogenetic, fluorescence in situ hybridization (FISH), and molecular analysis are usefu... more Combined cytogenetic, fluorescence in situ hybridization (FISH), and molecular analysis are useful in the diagnosis of sex chromosome aberrations. These methods were used in karyotype analysis of a 4-year-old girl with mild dysmorphism and growth retardation. Standard cytogenetic and FISH analysis was done on slides obtained from peripheral blood lymphocyte culture, and the molecular study was performed by using DNA polymorphism analysis. Both parents had normal karyotypes. Chromosome analysis of the proband identified the karyotype with 46 chromosomes and a late replicating dicentric X. Interphase FISH with an alpha satellite X centromere probe revealed two mosaic cell lines. Three signals were observed at 84.5% and one signal at 15.5% of the interphase cells. Molecular analysis showed that the dicentric X chromosome was of paternal origin. Based on this study, we concluded that the karyotype of the patient was 45,X/46,X, psu idic(X)(q22.3), with the trisomy Xpter-->q22.3 and mo...
Osteogenesis imperfecta (OI), or brittle bone disease, is a heritable disorder characterized by i... more Osteogenesis imperfecta (OI), or brittle bone disease, is a heritable disorder characterized by increased bone fragility. Four different types of the disease are commonly distinguished, ranging from a mild condition (type I) to a lethal one (type II). Types III and IV are the severe forms surviving the neonatal period. In most cases, there is a reduction in the production of normal type I collagen or the synthesis of abnormal collagen as a result of mutations in the type I collagen genes. These classic forms of OI are described in this review. There are instances, however, where alterations in bone matrix components, other than type I collagen, are the basic abnormalities of the OI. Recently, three such discrete types have been identified by histomorphometric evaluation (types V and VI) and linkage analysis (Rhizomelic OI). They provide evidence for the as yet poorly understood complexity of the phenotype-genotype correlation in OI. We also discuss bisphosphonates treatment as well ...
Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common cause of congenital adrena... more Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common cause of congenital adrenal hyperplasia. Mutations in theCYP11B1gene, which encodes steroid 11β-hydroxylase, are responsible for this autosomal recessive disorder. Here, we describe the molecular genetics of two previously reported male siblings in whom diagnosis of 11β-OHD has been established based on their hormonal profiles displaying high levels of 11-deoxycortisol and hyperandrogenism. Both patients are compound heterozygous for a novel p.E67fs (c.199delG) mutation in exon 1 and a p.R448H (c.1343G>A) mutation in exon 8. We also report the biochemical and molecular genetics data of one new 11β-OHD patient. Sequencing of theCYP11B1gene reveals that this patient is compound heterozygous for a novel, previously undescribed p.R141Q (c.422G>A) mutation in exon 3 and a p.T318R (c.953C>G) mutation in exon 5. All three patients are of Croatian (Slavic) origin and there is no self-reported consanguinity in th...
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