ABSTRACT
Carriers of apparently balanced chromosomal rearrangements (ABCRs) have a 2-3-fold higher risk of carrying an abnormal phenotype, when compared to the average population. Apparently balanced chromosomal rearrangements can be imbalanced at the submicroscopic level, and changes in the gene structure, formation of a new chimeric gene, gain or loss of function of the genes and altered imprinting pattern may also affect the phenotype. Chromosomal microarray (CMA) is an efficient tool to detect submicroscopic imbalances at the breakpoints as well as in the whole genome. We aimed to determine the effectiveness of array-comparative genomic hybridization (aCGH) application in phenotypically affected cases with ABCRs at a single center from Turkey. Thirty-four affected cases (13 prenatal, 21 postnatal) carrying ABCRs were investigated with CMA. In postnatal series, ABCRs were familial in 7 and de novo in 14 cases. Seven de novo cases were imbalanced (in postnatal series 33.3% and in de novo cases 50.0%). Out of 13 prenatal cases, five were familial and eight were de novo in origin and two de novo cases were imbalanced (in 15.4% prenatal series and in 25.0% de novo cases). No cryptic imbalance was observed in familial cases. The anomaly rates with array studies ranged between 14.3-25.0% in familial and between 20.0-57.5% in de novo cases of postnatal series in the literature. Studies focused on prenatal ABCR cases with abnormal ultrasound findings are limited and no submicroscopic imbalance was reported in the cohorts. When de novo postnatal or prenatal results were combined, the percentage of abnormalities detected by CMA was 40.9%. Taking this contribution into consideration, all ABCRs should be investigated by CMA even if the fetal ultrasound findings are normal.
ABSTRACT
We genetically evaluated 260 dystrophinopathy patients from Turkey. Karyotyping as an initial test in female patients, followed stepwise by multiplex ligation-dependent probe amplification and by targeted next-generation sequencing of DMD revealed definitive genetic diagnoses in 214 patients (82%), with gross deletions/duplications in 153 (59%), pathogenic sequence variants in 60 (23%), and X-autosome translocation in one. Seven of the gross and 27 of the sequence variants found novel. In silico prediction, co-segregation and transcript assays supported the pathogenic nature of the novel silent (p.Lys534=) and the splice site (c.4345-12C>G) alterations. From a total of 189 singleton cases, 154 (82%) had pathogenic alterations. From 138 of those who had maternal carrier testing, 68 out of 103 (66%) showed gross and 11 out of 35 (31%) showed small pathogenic variants. This suggests that the de novo occurrences in DMD appear approximately 2.1 times more frequently in meiotic unequal crossing-over than in uncorrected replication errors. Our study also disclosed three mothers as obligate gonadal mosaic carriers. Family-based investigation of dystrophinopathy patients is crucial for the ascertainment of novel or rare variants and also for counseling and follow-up care of the families.
Subject(s)
Dystrophin/genetics , Genetic Counseling , Muscular Dystrophy, Duchenne/genetics , Muscular Dystrophy, Duchenne/physiopathology , Adult , Child , Child, Preschool , Cohort Studies , Female , High-Throughput Nucleotide Sequencing , Humans , Infant , Male , Mutation , Phenotype , Sequence Analysis, DNA , Turkey , Young AdultABSTRACT
Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.
Subject(s)
Anodontia/genetics , Female , Genetic Linkage/genetics , Genetic Variation/genetics , Humans , Intercellular Signaling Peptides and Proteins/genetics , Laminin/genetics , Low Density Lipoprotein Receptor-Related Protein-6/genetics , Male , Membrane Proteins/genetics , Mutation, Missense/genetics , Pedigree , Real-Time Polymerase Chain Reaction , Turkey , Exome Sequencing/methods , Wnt Proteins/geneticsABSTRACT
Some of the disorders of sex development (DSD), including 46, XX testicular DSD formerly called "XX maleness" and 46, XY DSD with partial or complete gonadal dysgenesis primarily affect the gonads. Genetic alterations in ten unrelated females with complete 46, XY gonadal dysgenesis (GD) were analyzed using an Array 2.7 M platform with whole genome coverage. The analysis result suggested that the most significant region maps to chromosome 8q24.3 which were previously reported by another independent study with a similar patient cohort and this region being probable candidate related to complete 46, XY GD.
Subject(s)
Chromosome Duplication/genetics , Chromosomes, Human, Pair 8/genetics , Disorders of Sex Development/genetics , Gonadal Dysgenesis, 46,XY/genetics , Testis/abnormalities , Chromosome Mapping , Cohort Studies , Comparative Genomic Hybridization , Disorders of Sex Development/diagnosis , Female , Genome-Wide Association Study , Gonadal Dysgenesis, 46,XY/diagnosis , Humans , Karyotyping , Polymorphism, Genetic/genetics , TurkeyABSTRACT
BACKGROUND: Offspring of consanguineous couples are at increased risk of congenital disorders. The risk increases as parents are more closely related. Individuals that have the same degree of relatedness according to their pedigree, show variable genomic kinship coefficients. To investigate whether we can differentiate between couples with high- and low risk for offspring with congenital disorders, we have compared the genomic kinship coefficient of consanguineous parents with a child affected with an autosomal recessive disorder with that of consanguineous parents with only healthy children, corrected for the degree of pedigree relatedness. METHODS: 151 consanguineous couples (73 cases and 78 controls) from 10 different ethnic backgrounds were genotyped on the Affymetrix platform and passed quality control checks. After pruning SNPs in linkage disequilibrium, 57,358 SNPs remained. Kinship coefficients were calculated using three different toolsets: PLINK, King and IBDelphi, yielding five different estimates (IBDelphi, PLINK (all), PLINK (by population), King robust (all) and King homo (by population)). We performed a one-sided Mann Whitney test to investigate whether the median relative difference regarding observed and expected kinship coefficients is bigger for cases than for controls. Furthermore, we fitted a mixed effects linear model to correct for a possible population effect. RESULTS: Although the estimated degrees of genomic relatedness with the different toolsets show substantial variability, correlation measures between the different estimators demonstrated moderate to strong correlations. Controls have higher point estimates for genomic kinship coefficients. The one-sided Mann Whitney test did not show any evidence for a higher median relative difference for cases compared to controls. Neither did the regression analysis exhibit a positive association between case-control status and genomic kinship coefficient. CONCLUSIONS: In this case-control setting, in which we compared consanguineous couples corrected for degree of pedigree relatedness, a higher degree of genomic relatedness was not significantly associated with a higher likelihood of having an affected child. Further translational research should focus on which parts of the genome and which pathogenic mutations couples are sharing. Looking at relatedness coefficients by determining genome-wide SNPs does not seem to be an effective measure for prospective risk assessment in consanguineous parents.
Subject(s)
Congenital Abnormalities/genetics , Consanguinity , Genes, Recessive , Genome, Human/genetics , Base Sequence , Case-Control Studies , Female , Genotype , Humans , Male , Pedigree , Polymorphism, Single Nucleotide , Sequence Analysis, DNA , Statistics, NonparametricABSTRACT
Robinow Syndrome (RS), a rare skeletal dysplasia syndrome, is characterized by dysmorphic features resembling a fetal face, mesomelic limb shortening, hypoplastic external genitalia in males, and renal and vertebral anomalies. Both autosomal dominant and autosomal recessive patterns of inheritance have been reported. Since the description of autosomal dominant Robinow Syndrome (ADRS; OMIM 180700) in 1969 by Meinhard Robinow and colleagues, the molecular etiology remained elusive until only recently. WNT5A was proposed to be the candidate gene for ADRS, as mutations were found in two affected families, one of those being the originally described index family. We report three families with RS caused by novel heterozygous WNT5A mutations, which were confirmed in the first family by whole exome sequencing, and in all by Sanger sequencing. To our knowledge, this is the largest number of published families with ADRS in whom a WNT5A mutation was identified. Families 1 and 2 are the first cases showing de novo inheritance in the affected family members and thus strengthen the evidence for WNT5A as the causative gene in ADRS. Finally, we propose WNT5A mutation specificity in ADRS, which may affect interactions with other proteins in the Wnt pathway.
Subject(s)
Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/pathology , Dwarfism/genetics , Dwarfism/pathology , Limb Deformities, Congenital/genetics , Limb Deformities, Congenital/pathology , Models, Molecular , Phenotype , Proto-Oncogene Proteins/genetics , Urogenital Abnormalities/genetics , Urogenital Abnormalities/pathology , Wnt Proteins/genetics , Base Sequence , Exome/genetics , Gene Frequency , Genotype , Humans , Male , Molecular Sequence Data , Pedigree , Proto-Oncogene Proteins/chemistry , Sequence Analysis, DNA , Wnt Proteins/chemistry , Wnt-5a ProteinABSTRACT
Heterozygous loss-of-function mutations of GDF5 are reported to cause hypoplasia/aplasia of certain skeletal elements (brachydactyly), and heterozygous gain-of-function mutations, occurring either on the gene itself or through the loss of its inhibitor noggin, result in joint fusion (symphalangism). We present here the clinical and molecular investigation of a family with disproportionate shortness of the second and third fingers which comprises 9 variably affected members spanning 4 generations. In this study, we performed clinical and radiographical examinations of 2 patients of this family, sequencing of GDF5 and 3D protein modeling of the wildtype and mutated polypeptide to predict the structural alteration. Diagnoses were compatible with familial brachydactyly type C. GDF5 analysis revealed a novel heterozygous in-frame indel mutation (c.803_ 827del25ins25), involving the propeptide domain of GDF5 that alters the number of random coil and beta-strand structures, creating a 1-turn-helix at the mutated site. The mutation described here is the second indel reported in GDF5. The previously published homozygous indel mutation affected the TGF-beta like domain and was associated with Du Pan syndrome. The novel mutation reported here presents further allelic heterogeneity and a probable intrafamilial variable clinical expressivity of GDF5.
ABSTRACT
The lymphedema-lymphangiectasia-intellectual disability (Hennekam) syndrome (HS) is characterised by a widespread congenital lymph vessel dysplasia manifesting as congenital lymphedema of the limbs and intestinal lymphangiectasia, accompanied by unusual facial morphology, variable intellectual disabilities and infrequently malformations. The syndrome is heterogeneous as mutations in the gene CCBE1 have been found responsible for the syndrome in only a subset of patients. We investigated whether it would be possible to predict the presence of a CCBE1 mutation based on phenotype by collecting clinical data of patients diagnosed with HS, with or without a CCBE1 mutation. We report here the results of 13 CCBE1 positive patients, 16 CCBE1 negative patients, who were clinically found to have classical HS, and 8 patients in whom the diagnosis was considered possible, but not certain, and in whom no CCBE1 mutation was identified. We found no statistically significant phenotypic differences between the 2 groups with the clinical HS phenotype, although the degree of lymphatic dysplasia tended to be more pronounced in the mutation positive group. We also screened 158 patients with less widespread and less pronounced forms of lymphatic dysplasia for CCBE1 mutations, and no mutation was detected in this group. Our results suggest that (1) CCBE1 mutations are present only in patients with a likely clinical diagnosis of HS, and not in patients with less marked forms of lymphatic dysplasia, and (2) that there are no major phenotypic differences between HS patients with or without CCBE1 mutations.
ABSTRACT
Nager syndrome (MIM #154400) is the best-known preaxial acrofacial dysostosis, mainly characterized by craniofacial and preaxial limb anomalies. The craniofacial abnormalities mainly consist of downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear anomalies, and cleft palate. The preaxial limb defects are characterized by radial and thumb hypoplasia or aplasia, duplication of thumbs and proximal radioulnar synostosis. Haploinsufficiency of SF3B4 (MIM *605593), which encodes SAP49, a component of the pre-mRNA spliceosomal complex, has recently been identified as the underlying cause of Nager syndrome. In our study, we performed exome sequencing in two and Sanger sequencing of SF3B4 in further ten previously unreported patients with the clinical diagnosis of Nager syndrome, including one familial case. We identified heterozygous SF3B4 mutations in seven out of twelve patients. Four of the seven mutations were shown to be de novo; in three individuals, DNA of both parents was not available. No familial mutations were discovered. Three mutations were nonsense, three were frameshift mutations and one T > C transition destroyed the translation start signal. In three of four SF3B4 negative families, EFTUD2 was analyzed, but no pathogenic variants were identified. Our results indicate that the SF3B4 gene is mutated in about half of the patients with the clinical diagnosis of Nager syndrome and further support genetic heterogeneity for this condition.
Subject(s)
Exome/genetics , Mandibulofacial Dysostosis/genetics , Mutation/genetics , RNA Precursors/genetics , RNA-Binding Proteins/genetics , Spliceosomes/genetics , Adolescent , Adult , Child, Preschool , Female , Genetic Association Studies , Humans , Infant , Male , Mandibulofacial Dysostosis/diagnosis , RNA Splicing FactorsSubject(s)
Abnormalities, Multiple/diagnostic imaging , Diseases in Twins/diagnosis , Goldenhar Syndrome/diagnosis , Lung Diseases/diagnostic imaging , Thorax/abnormalities , Diseases in Twins/pathology , Goldenhar Syndrome/pathology , Humans , Infant, Newborn , Lung/abnormalities , Lung/diagnostic imaging , Male , Phenotype , Radiography , TwinsABSTRACT
OBJECTIVE: We sought to create a classification system for pediatric corpus callosal abnormalities (CCA) based upon midline sagittal brain MRI. We used the term CCA for patients with structural variants of the corpus callosum, excluding patients with interhemispheric cyst variant or pure dysplasia without hypoplasia. Currently, no system exists for nonsyndromic forms of CCA, and attempts to create such a system have been hampered by highly variable morphology in patients with sporadic CCA. We reasoned that any useful strategy should classify affected family members within the same type, and that phenotypic variability should be minimized in patients with recessive disease. METHODS: We focused recruitment toward multiplex consanguineous families, ascertained 30 patients from 19 consanguineous families, and analyzed clinical features together with brain imaging. RESULTS: We identified 3 major CCA classes, including hypoplasia, hypoplasia with dysplasia, and complete agenesis. Affected individuals within a given multiplex family usually displayed the same variant of the class of abnormality and they always displayed the same class of abnormality within each family, or they displayed complete agenesis. The system was validated among a second cohort of 10 sporadic patients with CCA. CONCLUSIONS: The data suggest that complete agenesis may be a common end-phenotype, and implicate multiple overlapping pathways in the etiology of CCA.
Subject(s)
Agenesis of Corpus Callosum , Consanguinity , Nervous System Malformations/classification , Aicardi Syndrome/classification , Child , Humans , Magnetic Resonance ImagingABSTRACT
BACKGROUND: Roberts syndrome (RBS) and SC phocomelia are caused by mutations in ESCO2, which codes for an acetyltransferase involved in the regulation of sister chromatid cohesion. Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be truncating mutations. Genotype-phenotype analysis has been hampered by limited numbers of patients with clinical information available. OBJECTIVE: To provide unpublished clinical data for 31 patients with proven ESCO2 mutations and combine this series with previously reported clinical and mutation data on 18 cases. Methods Genotype-phenotype correlations and functional effects of two novel ESCO2 mutations were analysed. In situ hybridisation on human embryos at Carnegie stages 14, 17 and 21 was performed to study ESCO2 expression during development. RESULTS AND CONCLUSIONS: Using the cohort of 49 patients, the clinical criteria for RBS were delineated to include: growth retardation; symmetric mesomelic shortening of the limbs in which the upper limbs are more commonly and severely affected than the lower limbs; characteristic facies with microcephaly. The severity of malformations of the facies correlates with the severity of limb reduction. The occurrence of corneal opacities may be associated with specific mutations. Two new mutations, both in the ESCO2 acetyltransferase domain, are described and their acetylation effects in vitro demonstrated. In situ hybridisation on human embryos showed ESCO2 expression in the brain, face, limb, kidney and gonads, which corresponds to the structures affected in RBS.
Subject(s)
Abnormalities, Multiple/genetics , Acetyltransferases/genetics , Chromosomal Proteins, Non-Histone/genetics , Craniofacial Abnormalities/genetics , Developmental Disabilities/genetics , Intellectual Disability/genetics , Codon/genetics , Female , Gene Expression , Genetic Variation , Humans , Infant , Male , Mutation, Missense , Phenotype , Protein Structure, Tertiary/genetics , Sequence Deletion , SyndromeABSTRACT
BACKGROUND: Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive disorder characterised by the five cardinal features retinitis pigmentosa, postaxial polydactyly, mental retardation, obesity and hypogenitalism. In addition, renal cysts and other anomalies of the kidney and urinary tract can be present. To date, mutations in 12 BBS genes as well as in MKS1 and CEP290 have been identified as causing BBS. The vast genetic heterogeneity of BBS renders molecular genetic diagnosis difficult in terms of the time and cost required to screen all 204 coding exons. METHOD: Here, the use of genome-wide homozygosity mapping as a tool to identify homozygous segments at known BBS loci, in BBS individuals from inbred and outbred background, is reported. RESULTS: In a worldwide cohort of 45 families, causative homozygous mutations in 20 families were identified via direct exon sequencing. Eleven of these mutations were novel, thereby increasing the number of known BBS mutations by 5% (11/218). CONCLUSIONS: Thus, in the presence of extreme genetic locus heterogeneity, homozygosity mapping provides a valuable approach to the molecular genetic diagnosis of BBS and will facilitate the discovery of novel pathogenic mutations.
Subject(s)
Bardet-Biedl Syndrome/genetics , Mutation , Amino Acid Sequence , Base Sequence , Chromosome Mapping/methods , Cohort Studies , Consanguinity , Genetic Association Studies , Genome, Human , Homozygote , Humans , Molecular Sequence Data , Phenotype , Proteins/geneticsABSTRACT
BACKGROUND: Schneckenbecken dysplasia (SBD) is an autosomal recessive lethal skeletal dysplasia that is classified into the severe spondylodysplastic dysplasias (SSDD) group in the international nosology for skeletal dysplasias. The radiological hallmark of SBD is the snail-like configuration of the hypoplastic iliac bone. SLC35D1 (solute carrier-35D1) is a nucleotide-sugar transporter involved in proteoglycan synthesis. Recently, based on human and mouse genetic studies, we showed that loss-of-function mutations of the SLC35D1 gene (SLC35D1) cause SBD. OBJECT: To explore further the range of SLC35D1 mutations in SBD and elucidate whether SLC35D1 mutations cause other skeletal dysplasias that belong to the SSDD group. METHODS AND RESULTS: We searched for SLC35D1 mutations in five families with SBD and 15 patients with other SSDD group diseases, including achodrogenesis type 1A, spondylometaphyseal dysplasia Sedaghatian type and fibrochondrogenesis. We identified four novel mutations, c.319C>T (p.R107X), IVS4+3A>G, a 4959-bp deletion causing the removal of exon 7 (p.R178fsX15), and c.193A>C (p. T65P), in three SBD families. Exon trapping assay showed IVS4+3A>G caused skipping of exon 4 and a frameshift (p.L109fsX18). Yeast complementation assay showed the T65P mutant protein lost the transporter activity of nucleotide sugars. Therefore, all these mutations result in loss of function. No SLC35D1 mutations were identified in all patients with other SSDD group diseases. CONCLUSION: Our findings suggest that SLC35D1 loss-of-function mutations result consistently in SBD and are exclusive to SBD.
Subject(s)
Bone Diseases, Developmental/genetics , Fetal Diseases/genetics , Gene Deletion , Monosaccharide Transport Proteins/genetics , Mutation , Base Sequence , Cloning, Molecular , Female , Humans , Male , Molecular Sequence Data , Nucleotides/metabolism , Polymerase Chain Reaction , Pregnancy , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Sequence AlignmentABSTRACT
BACKGROUND: Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous condition characterised by severe intrauterine and postnatal growth retardation. Loss of DNA methylation at the telomeric imprinting control region 1 (ICR1) on 11p15 is an important cause of SRS. METHODS: We studied the methylation pattern at the H19-IGF2 locus in 201 patients with suspected SRS. In an attempt to categorise the patients into different subgroups, we developed a simple clinical scoring system with respect to readily and unambiguously assessable clinical features. In a second step, the relationship between clinical score and epigenetic status was analysed. RESULTS AND CONCLUSIONS: The scoring system emerged as a powerful tool for identifying those patients with both a definite SRS phenotype and carrying an epimutation at 11p15. 53% of the 201 patients initially enrolled fulfilled the criteria for SRS and about 40% of them exhibited an epimutation at the H19-IGF2 locus. Methylation defects were restricted to patients who fulfilled the diagnostic criteria for SRS. Patients carrying epimutations had a more severe phenotype than either the SRS patients with mUPD7 or the idiopathic SRS patients. The majority of patients with methylation abnormalities showed hypomethylation at both the H19 and IGF2 genes. However, we also identified SRS patients where hypomethylation was restricted to either the H19 or the IGF2 gene. Interestingly, we detected epimutations in siblings of normal parents, most likely reflecting germ cell mosaicism in the fathers. In one family, we identified an epimutation in an affected father and his likewise affected daughter.
Subject(s)
Abnormalities, Multiple/genetics , Epigenesis, Genetic , Insulin-Like Growth Factor II/genetics , Mutation , Adolescent , Adult , Analysis of Variance , Child , Child, Preschool , Cohort Studies , Craniofacial Abnormalities/genetics , DNA Methylation , Female , Fetal Growth Retardation/genetics , Genomic Imprinting , Humans , Infant , Male , Phenotype , Pregnancy , Research Design , Syndrome , Uniparental DisomyABSTRACT
BACKGROUND: Recessive forms of osteogenesis imperfecta (OI) may be caused by mutations in LEPRE1, encoding prolyl 3-hydroxylase-1 (P3H1) or in CRTAP, encoding cartilage associated protein. These proteins constitute together with cyclophilin B (CyPB) the prolyl 3-hydroxylation complex that hydroxylates the Pro986 residue in both the type I and type II collagen alpha1-chains. METHODS: We screened LEPRE1, CRTAP and PPIB (encoding CyPB) in a European/Middle Eastern cohort of 20 lethal/severe OI patients without a type I collagen mutation. RESULTS: Four novel homozygous and compound heterozygous mutations were identified in LEPRE1 in four probands. Two probands survived the neonatal period, including one patient who is the eldest reported patient (17 7/12 years) so far with P3H1 deficiency. At birth, clinical and radiologic features were hardly distinguishable from those in patients with autosomal dominant (AD) severe/lethal OI. Follow-up data reveal that the longer lived patients develop a severe osteochondrodysplasia that overlaps with, but has some distinctive features from, AD OI. A new splice site mutation was identified in two of the four probands, affecting only one of three LEPRE1 mRNA splice forms, detected in this study. The affected splice form encodes a 736 amino acid (AA) protein with a "KDEL" endoplasmic reticulum retention signal. While western blotting and immunocytochemical analysis of fibroblast cultures revealed absence of this P3H1 protein, mass spectrometry and SDS-urea-PAGE data showed severe reduction of alpha1(I)Pro986 3-hydroxylation and overmodification of type I (pro)collagen chains in skin fibroblasts of the patients. CONCLUSION: These findings suggest that the 3-hydroxylation function of P3H1 is restricted to the 736AA splice form.
Subject(s)
Membrane Glycoproteins/genetics , Mutation , Osteogenesis Imperfecta/genetics , Proteoglycans/genetics , Alternative Splicing , Blotting, Western , Cells, Cultured , Cohort Studies , Collagen Type I/metabolism , Cyclophilins/genetics , Cyclophilins/metabolism , DNA Mutational Analysis , Electrophoresis, Polyacrylamide Gel , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Fibroblasts/cytology , Fibroblasts/metabolism , Gene Expression , Genes, Recessive , Genetic Testing , Humans , Hydroxylation , Immunohistochemistry , Isoenzymes/genetics , Isoenzymes/metabolism , Membrane Glycoproteins/metabolism , Molecular Chaperones , Osteogenesis Imperfecta/diagnosis , Prolyl Hydroxylases , Proteoglycans/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tandem Mass SpectrometryABSTRACT
OBJECTIVE: To delineate a new syndrome of brain dysgenesis and cutis laxa based on the description of 11 patients belonging to nine unrelated families recruited through an international collaboration effort. METHODS: Careful clinical assessment of patients from birth to the age of 23 years with follow-up studies ranging from 3 to 20 years. Biochemical studies of serum proteins glycosylation by isoelectric focusing and capillary zone electrophoresis were performed in 10 patients. Brain MRI studies using conventional methods were analyzed in eight patients. RESULTS: An expanded clinical spectrum of a syndrome comprising facial dysmorphia (enlarged anterior fontanelles, downward slant of palpebral fissures, prominent root of the nose), a connective tissue disorder (inguinal hernia, hip dislocation, high myopia), and neurologic impairment was defined. Early developmental delay was followed by onset of generalized seizures by the end of the first decade and a subsequent neurodegenerative course. A defect of N- or N- plus O-glycosylation of serum transferrins and ApoCIII was observed in 10 patients. An unusual cobblestone-like cortical malformation over the frontal and parietal regions was seen in eight patients and cerebellar abnormalities, including two patients with Dandy-Walker malformation, were observed in three patients. CONCLUSIONS: Our results suggest that autosomal recessive cutis laxa, Debré type, initially considered a dermatologic syndrome, is a multisystemic disorder with cobblestone-like brain dysgenesis manifesting as developmental delay and an epileptic neurodegenerative syndrome. It might represent a metabolic cause of Dandy-Walker malformation. It is associated with a deficient N- and-O glycosylation of proteins and shares many similarities with muscle-eye-brain syndromes.
Subject(s)
Brain/abnormalities , Cutis Laxa , Dandy-Walker Syndrome , Adolescent , Brain/pathology , Child , Child, Preschool , Congenital Abnormalities/blood , Congenital Abnormalities/genetics , Congenital Abnormalities/pathology , Cutis Laxa/blood , Cutis Laxa/genetics , Cutis Laxa/pathology , Dandy-Walker Syndrome/blood , Dandy-Walker Syndrome/genetics , Dandy-Walker Syndrome/pathology , Electrophoresis, Capillary/methods , Female , Glycosylation , Humans , Infant , Infant, Newborn , Isoelectric Focusing/methods , Longitudinal Studies , Magnetic Resonance Imaging/methods , Male , Young AdultABSTRACT
Autosomal recessive inheritance of non-syndromic mental retardation (ARNSMR) may account for approximately 25% of all patients with non-specific mental retardation (NSMR). Although many X-linked genes have been identified as a cause of NSMR, only three autosomal genes are known to cause ARNSMR. We present here a large consanguineous Turkish family with four mentally retarded individuals from different branches of the family. Clinical tests showed cognitive impairment but no neurological, skeletal, and biochemical involvements. Genome-wide mapping using Human Mapping 10K Array showed a single positive locus with a parametric LOD score of 4.92 in a region on chromosome 1p21.1-p13.3. Further analyses using polymorphic microsatellite markers defined a 6.6-Mb critical region containing approximately 130 known genes. This locus is the fourth one linked to ARNSMR.
Subject(s)
Chromosome Mapping , Chromosomes, Human, Pair 1 , Genes, Recessive , Intellectual Disability/genetics , Consanguinity , Female , Genetic Linkage , Humans , Intellectual Disability/diagnosis , Lod Score , Male , Microsatellite Repeats , PedigreeABSTRACT
Leroy I-cell disease is a rare autosomal recessive lysosomal storage disorder characterized by marked psychomotor and growth retardation, skeletal anomalies, and typical facial features. There is a biochemical defect in uridine diphospho-N-acetylglucosamine-1-phosphotransferase, which is the enzyme responsible for addition of a mannose phosphate residue for lysosomal trafficking. Prenatal diagnosis is possible by analysis of enzyme activity in chorionic villi or cultured amniocytes, but this is offered to families only known to be at increased risk. We describe two cases that had bilateral shortness of the femurs at 25 and 31 weeks of gestation in the ultrasound scan and were diagnosed as Leroy I-cell disease by plasma enzyme analysis in the postnatal period. There was also bowing of the femurs in one case. None of the two families had a history of Leroy I-cell disease. The parents of one case were second-degree cousins. In view of these two cases that are presented, we propose that Leroy I-cell disease should be included in the differential diagnosis of short femurs even when there is no evident family history.