ABSTRACT
BACKGROUND: The clinical significance of 16p13.11 duplications remains controversial while frequently detected in patients with developmental delay (DD), intellectual deficiency (ID) or autism spectrum disorder (ASD). Previously reported patients were not or poorly characterised. The absence of consensual recommendations leads to interpretation discrepancy and makes genetic counselling challenging. This study aims to decipher the genotype-phenotype correlations to improve genetic counselling and patients' medical care. METHODS: We retrospectively analysed data from 16 013 patients referred to 12 genetic centers for DD, ID or ASD, and who had a chromosomal microarray analysis. The referring geneticists of patients for whom a 16p13.11 duplication was detected were asked to complete a questionnaire for detailed clinical and genetic data for the patients and their parents. RESULTS: Clinical features are mainly speech delay and learning disabilities followed by ASD. A significant risk of cardiovascular disease was noted. About 90% of the patients inherited the duplication from a parent. At least one out of four parents carrying the duplication displayed a similar phenotype to the propositus. Genotype-phenotype correlations show no impact of the size of the duplicated segment on the severity of the phenotype. However, NDE1 and miR-484 seem to have an essential role in the neurocognitive phenotype. CONCLUSION: Our study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of NDE1 and miR-484 in the neurocognitive phenotype. Moreover, it suggests the need for cardiac evaluation and follow-up and a large study to evaluate the aortic disease risk.
Subject(s)
Autism Spectrum Disorder/genetics , Developmental Disabilities/genetics , Intellectual Disability/genetics , MicroRNAs/genetics , Microtubule-Associated Proteins/genetics , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Adolescent , Adult , Autism Spectrum Disorder/pathology , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/genetics , Cardiovascular Diseases/pathology , Child , Child, Preschool , Chromosomes, Human, Pair 16/genetics , Developmental Disabilities/pathology , Female , Gene Duplication/genetics , Genetic Association Studies , Humans , Infant , Intellectual Disability/pathology , Male , Phenotype , Risk Factors , Young AdultABSTRACT
The Xq28 duplication involving the MECP2 gene (MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.
Subject(s)
Exotropia/genetics , Hypertension, Pulmonary/genetics , Intellectual Disability/genetics , Mental Retardation, X-Linked/genetics , Methyl-CpG-Binding Protein 2/genetics , Adolescent , Adult , Child , Child, Preschool , Chromosomes, Human, X/genetics , Developmental Disabilities/complications , Developmental Disabilities/genetics , Developmental Disabilities/physiopathology , Epilepsy/complications , Epilepsy/genetics , Epilepsy/physiopathology , Exotropia/complications , Exotropia/physiopathology , France/epidemiology , Humans , Hyperopia/complications , Hyperopia/genetics , Hyperopia/physiopathology , Hypertension, Pulmonary/complications , Hypertension, Pulmonary/physiopathology , Infant , Intellectual Disability/complications , Intellectual Disability/physiopathology , Male , Mental Retardation, X-Linked/complications , Mental Retardation, X-Linked/physiopathology , Pedigree , Phenotype , Somatosensory Disorders/genetics , Somatosensory Disorders/physiopathology , Stereotypic Movement Disorder/complications , Stereotypic Movement Disorder/genetics , Stereotypic Movement Disorder/physiopathology , Young AdultABSTRACT
BACKGROUND: SOX11 is a transcription factor proposed to play a role in brain development. The relevance of SOX11 to human developmental disorders was suggested by a recent report of SOX11 mutations in two patients with Coffin-Siris syndrome. Here we further investigate the role of SOX11 variants in neurodevelopmental disorders. METHODS: We used array based comparative genomic hybridisation and trio exome sequencing to identify children with intellectual disability who have deletions or de novo point mutations disrupting SOX11. The pathogenicity of the SOX11 mutations was assessed using an in vitro gene expression reporter system. Loss-of-function experiments were performed in xenopus by knockdown of Sox11 expression. RESULTS: We identified seven individuals with chromosome 2p25 deletions involving SOX11. Trio exome sequencing identified three de novo SOX11 variants, two missense (p.K50N; p.P120H) and one nonsense (p.C29*). The biological consequences of the missense mutations were assessed using an in vitro gene expression system. These individuals had microcephaly, developmental delay and shared dysmorphic features compatible with mild Coffin-Siris syndrome. To further investigate the function of SOX11, we knocked down the orthologous gene in xenopus. Morphants had significant reduction in head size compared with controls. This suggests that SOX11 loss of function can be associated with microcephaly. CONCLUSIONS: We thus propose that SOX11 deletion or mutation can present with a Coffin-Siris phenotype.
Subject(s)
Abnormalities, Multiple/genetics , Face/abnormalities , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Micrognathism/genetics , Neck/abnormalities , Neurodevelopmental Disorders/genetics , SOXC Transcription Factors/genetics , Sequence Deletion , Abnormalities, Multiple/physiopathology , Adolescent , Adult , Animals , Child , Child, Preschool , Face/physiopathology , Female , Gene Knockdown Techniques , Hand Deformities, Congenital/physiopathology , Humans , Intellectual Disability/physiopathology , Male , Microcephaly , Micrognathism/physiopathology , Neck/physiopathology , Neurodevelopmental Disorders/physiopathology , XenopusABSTRACT
Anophthalmia and microphthalmia (A/M) are early-eye-development anomalies resulting in absent or small ocular globes, respectively. A/M anomalies occur in syndromic or nonsyndromic forms. They are genetically heterogeneous, some mutations in some genes being responsible for both anophthalmia and microphthalmia. Using a combination of homozygosity mapping, exome sequencing, and Sanger sequencing, we identified homozygosity for one splice-site and two missense mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) in three consanguineous families segregating A/M with occasional orbital cystic, neurological, and cardiac anomalies. ALDH1A3 is a key enzyme in the formation of a retinoic acid gradient along the dorso-ventral axis during early eye development. Transitory expression of mutant ALDH1A3 open reading frames showed that both missense mutations reduce the accumulation of the enzyme, potentially leading to altered retinoic acid synthesis. Although the role of retinoic acid signaling in eye development is well established, our findings provide genetic evidence of a direct link between retinoic-acid-synthesis dysfunction and early-eye-development anomalies in humans.
Subject(s)
Aldehyde Dehydrogenase/genetics , Anophthalmos/enzymology , Anophthalmos/genetics , Genes, Recessive/genetics , Microphthalmos/enzymology , Microphthalmos/genetics , Mutation/genetics , Aldehyde Oxidoreductases , Chromosome Segregation/genetics , Exons/genetics , Female , Genetic Linkage , HEK293 Cells , Homozygote , Humans , Introns/genetics , Male , Mutant Proteins/metabolism , Pedigree , Sequence Analysis, DNAABSTRACT
Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2α (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.
Subject(s)
Abnormalities, Multiple/etiology , Branchio-Oto-Renal Syndrome/etiology , Ectodermal Dysplasia/etiology , Exome/genetics , Hypospadias/etiology , Muscle Hypotonia/etiology , Mutation, Missense/genetics , Repressor Proteins/genetics , Abnormalities, Multiple/pathology , Amino Acid Sequence , Branchio-Oto-Renal Syndrome/pathology , Co-Repressor Proteins , Ear, External/abnormalities , Ear, External/pathology , Ectodermal Dysplasia/pathology , Female , Humans , Hypospadias/pathology , Male , Molecular Sequence Data , Muscle Hypotonia/pathology , Nipples/abnormalities , Nipples/pathology , Pedigree , Phenotype , Protein Structure, Tertiary , Scalp/abnormalities , Scalp/pathology , Sequence Homology, Amino AcidABSTRACT
Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability, stereotyped movements, and recurrent pulmonary infections. We report on standardized brain magnetic resonance imaging (MRI) data of 30 affected patients carrying an Xq28 duplication involving MECP2 of various sizes (228 kb to 11.7 Mb). The aim of this study was to seek recurrent malformations and attempt to determine whether variations in imaging features could be explained by differences in the size of the duplications. We showed that 93% of patients had brain MRI abnormalities such as corpus callosum abnormalities (n = 20), reduced volume of the white matter (WM) (n = 12), ventricular dilatation (n = 9), abnormal increased hyperintensities on T2-weighted images involving posterior periventricular WM (n = 6), and vermis hypoplasia (n = 5). The occipitofrontal circumference varied considerably between >+2SD in five patients and <-2SD in four patients. Among the nine patients with dilatation of the lateral ventricles, six had a duplication involving L1CAM. The only patient harboring bilateral posterior subependymal nodular heterotopia also carried an FLNA gene duplication. We could not demonstrate a correlation between periventricular WM hyperintensities/delayed myelination and duplication of the IKBKG gene. We thus conclude that patients with an Xq28 duplication involving MECP2 share some similar but non-specific brain abnormalities. These imaging features, therefore, could not constitute a diagnostic clue. The genotype-phenotype correlation failed to demonstrate a relationship between the presence of nodular heterotopia, ventricular dilatation, WM abnormalities, and the presence of FLNA, L1CAM, or IKBKG, respectively, in the duplicated segment.
Subject(s)
Brain Diseases/genetics , Chromosomes, Human, X/genetics , Gene Duplication , Magnetic Resonance Imaging/methods , Mental Retardation, X-Linked/genetics , Methyl-CpG-Binding Protein 2/genetics , Adolescent , Adult , Brain Diseases/pathology , Child , Child, Preschool , Female , Genetic Association Studies , Genotype , Humans , Infant , Infant, Newborn , Male , Mental Retardation, X-Linked/pathology , Middle Aged , Pedigree , Phenotype , Prognosis , Young AdultABSTRACT
Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome sequencing, we identified a dominantly inherited heterozygous in-frame deletion in exon 1 of SKI. Direct sequencing of SKI further identified one overlapping heterozygous in-frame deletion and ten heterozygous missense mutations affecting recurrent residues in 18 of the 19 individuals screened for SGS; these individuals included one family affected by somatic mosaicism. All mutations were located in a restricted area of exon 1, within the R-SMAD binding domain of SKI. No mutation was found in a cohort of 11 individuals with other marfanoid-craniosynostosis phenotypes. The interaction between SKI and Smad2/3 and Smad 4 regulates TGF-ß signaling, and the pattern of anomalies in Ski-deficient mice corresponds to the clinical manifestations of SGS. These findings define SGS as a member of the family of diseases associated with the TGF-ß-signaling pathway.
Subject(s)
Arachnodactyly/genetics , Craniosynostoses/genetics , DNA-Binding Proteins/genetics , Exons , Genes, Dominant , Marfan Syndrome/genetics , Mutation , Proto-Oncogene Proteins/genetics , Adolescent , Adult , Amino Acid Sequence , Child , Child, Preschool , DNA-Binding Proteins/chemistry , Facies , Female , Gene Order , Humans , Male , Models, Molecular , Molecular Sequence Data , Pedigree , Phenotype , Protein Structure, Tertiary , Proto-Oncogene Proteins/chemistry , Sequence Alignment , Young AdultABSTRACT
Albright hereditary osteodystrophy (AHO)-like syndrome is also known as brachydactyly-mental retardation syndrome (BDMR; OMIM 60040). This disorder includes intellectual disability in all patients, skeletal abnormalities, including brachydactyly E (BDE) in approximately half, obesity, and facial dysmorphism. Patients with 2q37 microdeletion or HDAC4 mutation are defined as having an AHO-like phenotype with normal stimulatory G (Gs) function. HDAC4 is involved in neurological, cardiac, and skeletal function. This paper reports the first familial case of 2q37.3 interstitial deletion affecting two genes, HDAC4 and TWIST2. Patients presented with BDE and short stature without intellectual disability, showing that haploinsufficiency of the HDAC4 critical region may lead to a spectrum of phenotypes, ranging from isolated brachydactyly type E to BDMR.
Subject(s)
Body Height , Bone and Bones/abnormalities , Brachydactyly/genetics , Inheritance Patterns/genetics , Brachydactyly/diagnostic imaging , Child , Chromosome Deletion , Chromosomes, Human, Pair 2/genetics , Family , Female , Genome, Human , Humans , Infant , Infant, Newborn , Male , Pedigree , RadiographyABSTRACT
West syndrome is a well-recognized form of epilepsy, defined by a triad of infantile spasms, hypsarrhythmia and developmental arrest. West syndrome is heterogenous, caused by mutations of genes ARX, STXBP1, KCNT1 among others; 16p13.11 and 17q21.31 microdeletions are less frequent, usually associated with intellectual disability and facial dysmorphism. So-called "idiopathic" West syndrome is of better prognostic, without prior intellectual deficiency and usually responsive to anti-epileptic treatment. We report on a boy falling within the scope of idiopathic West syndrome, with no dysmorphic features and normal development before the beginning of West syndrome, with a good resolution after treatment, bearing a de novo 15q13.3 microdeletion. Six genes are located in the deleted region, including CHRNA7, which encodes a subunit of a nicotinic acetylcholine receptor, and is frequently associated with epilepsy. Exploration of the 15q13.3 region should be proposed in idiopathic West syndrome.
Subject(s)
Chromosome Disorders/complications , Intellectual Disability/complications , Seizures/complications , Spasms, Infantile/complications , Adult , Chromosome Deletion , Chromosome Disorders/diagnosis , Chromosomes, Human, Pair 15 , Comparative Genomic Hybridization , Electroencephalography , Facies , Female , Humans , Infant , Infant, Newborn , Intellectual Disability/diagnosis , Male , Seizures/diagnosis , Spasms, Infantile/diagnosis , alpha7 Nicotinic Acetylcholine Receptor/geneticsABSTRACT
We present three patients with overlapping interstitial deletions of 19p13.3 identified by high resolution SNP microarray analysis. All three had a similar phenotype characterized by intellectual disability or developmental delay, structural heart abnormalities, large head relative to height and weight or macrocephaly, and minor facial anomalies. Deletion sizes ranged from 792 Kb to 1.0 Mb and included a common region arr [hg19] 19p13.3 (3,814,392-4,136,989), containing eight genes: ZFR2, ATCAY, NMRK2, DAPK3, EEF2, PIAS4, ZBTB7A, MAP2K2, and two non-coding RNA's MIR637 and SNORDU37. The patient phenotypes were compared with three previous single patient reports with similar interstitial 19p13.3 deletions and six additional patients from the DECIPHER and ISCA databases to determine if a common haploinsufficient phenotype for the region can be established.
Subject(s)
Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 19/genetics , Developmental Disabilities/genetics , Intellectual Disability/genetics , Polymorphism, Single Nucleotide/genetics , Sequence Deletion/genetics , Child , Child, Preschool , Female , Humans , In Situ Hybridization, Fluorescence , Male , Microarray Analysis , Young AdultABSTRACT
Ectodermal dysplasias (ED) are a clinically and genetically heterogeneous group of hereditary disorders that have in common abnormal development of ectodermal derivatives. Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of eccrine sweat glands, hair, and teeth. The X-linked form of the disease, caused by mutations in the EDA gene, represents the majority of patients with the hypohidrotic form. Autosomal dominant and autosomal recessive forms are occasionally seen, and result from mutations in at least three genes (WNT10A, EDAR, or more rarely EDARADD). We have screened for mutations in EDAR (commonly involved in the hypohidrotic form) and WNT10A (involved in a wide spectrum of ED and in isolated hypodontia) in a cohort of 36 patients referred for EDA molecular screening, which failed to identify any mutation. We identified eight EDAR mutations in five patients (two with homozygous mutations, one with compound heterozygous mutations, and two with heterozygous mutation), four of which were novel variants. We identified 28 WNT10A mutations in 16 patients (5 with homozygous mutations, 7 with compound heterozygous mutations, and 4 with heterozygous mutations), seven of which were novel variants. Our study allows a more precise definition of the phenotypic spectrum associated with EDAR and WNT10A mutations and underlines the importance of the implication of WNT10A among patients with ED.
Subject(s)
Anodontia/genetics , Ectodermal Dysplasia/genetics , Mutation , Wnt Proteins/genetics , Amino Acid Sequence , Anodontia/complications , Ectodermal Dysplasia/complications , Edar Receptor/genetics , Female , Genetic Association Studies , Genotype , Humans , Male , Molecular Sequence Data , Phenotype , Sequence AlignmentABSTRACT
Germline heterozygous alterations of the tumor-suppressor gene neurofibromatosis-1 (NF1) lead to neurofibromatosis type 1, a genetic disorder characterized by a higher risk to develop juvenile myelomonocytic leukemia and/or acute myeloid leukemia (AML). More recently, somatic 17q11 deletions encompassing NF1 have been described in many adult myeloid malignancies. In this context, we aimed to define NF1 involvement in AML. We screened a total of 488 previously untreated de novo AML patients for the NF1 deletion using either array comparative genomic hybridization (aCGH) or real-time quantitative PCR/fluorescence in situ hybridization approaches. We also applied massively parallel sequencing for in depth mutation analysis of NF1 in 20 patients including five NF1-deleted patients. We defined a small â¼0.3 Mb minimal deleted region involving NF1 by aCGH and an overall frequency of NF1 deletion of 3.5% (17/485). NF1 deletion is significantly associated with unfavorable cytogenetics and with monosomal karyotype notably. We discovered six NF1 variants of unknown significance in 7/20 patients of which only one out of four disappeared in corresponding complete remission sample. In addition, only one out of five NF1-deleted patients has an acquired coding mutation in the remaining allele. In conclusion, direct NF1 inactivation is infrequent in de novo AML and may be a secondary event probably involved in leukemic progression.
Subject(s)
Gene Deletion , Leukemia, Myeloid, Acute/genetics , Neurofibromatosis 1/genetics , Neurofibromin 1/genetics , Adolescent , Adult , Aged , Alleles , Comparative Genomic Hybridization , Female , Gene Frequency , High-Throughput Nucleotide Sequencing , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Male , Middle Aged , Mutation Rate , Neurofibromin 1/deficiency , Real-Time Polymerase Chain ReactionABSTRACT
BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder predisposing humans to cutaneous and uterine leiomyomas; in 20% of affected families, type 2 papillary renal cell cancers (PRCCII) also occur with aggressive course and poor prognosis. HLRCC results from heterozygous germline mutations in the tumour suppressor fumarate hydratase (FH) gene. METHODS: As part of the French National Cancer Institute (INCa) 'Inherited predispositions to kidney cancer' network, sequence analysis and a functional study of FH were preformed in 56 families with clinically proven or suspected HLRCC and in 23 patients with isolated PRCCII (5 familial and 18 sporadic). RESULTS: The study identified 32 different germline FH mutations (15 missense, 6 frameshifts, 4 nonsense, 1 deletion/insertion, 5 splice site, and 1 complete deletion) in 40/56 (71.4%) families with proven or suspected HLRCC and in 4/23 (17.4%) probands with PRCCII alone, including 2 sporadic cases. 21 of these were novel and all were demonstrated as deleterious by significant reduction of FH enzymatic activity. In addition, 5 asymptomatic parents in 3 families were confirmed as carrying disease-causing mutations. CONCLUSIONS: This study identified and characterised 21 novel FH mutations and demonstrated that PRCCII can be the only one manifestation of HLRCC. Due to the incomplete penetrance of HLRCC, the authors propose to extend the FH mutation analysis to every patient with PRCCII occurring before 40 years of age or when renal tumour harbours characteristic histologic features, in order to discover previously ignored HLRCC affected families.
Subject(s)
Carcinoma, Renal Cell/genetics , Fumarate Hydratase/genetics , Kidney Neoplasms/genetics , Mutation , Adult , Aged , Cell Line, Tumor , Codon, Nonsense , Female , Frameshift Mutation , Gene Deletion , Gene Rearrangement , Genotype , Germ-Line Mutation , Humans , INDEL Mutation , Leiomyomatosis/congenital , Leiomyomatosis/genetics , Male , Middle Aged , Mutation, Missense , Neoplastic Syndromes, Hereditary , Pedigree , Skin Neoplasms , Uterine NeoplasmsABSTRACT
OBJECTIVE: Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations. METHODS: Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%). ColVI secretion was analyzed in patient-derived skin fibroblasts. Chain-specific transcript levels were quantified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and mutation identification was performed by sequencing of complementary DNA. RESULTS: ColVI secretion was altered in all fibroblast cultures studied. We identified 56 mutations, mostly novel and private. Dominant de novo mutations were detected in 61% of the cases. Importantly, mutations causing premature termination codons (PTCs) or in-frame insertions strikingly destabilized the corresponding transcripts. Homozygous PTC-causing mutations in the triple helix domains led to the most severe phenotypes (ambulation never achieved), whereas dominant de novo in-frame exon skipping and glycine missense mutations were identified in patients of the moderate-progressive group (loss of ambulation). INTERPRETATION: This work emphasizes that the diagnosis of early onset ColVI myopathies is arduous and time-consuming, and demonstrates that quantitative RT-PCR is a helpful tool for the identification of some mutation-bearing genes. Moreover, the clinical classification proposed allowed genotype-phenotype relationships to be explored, and may be useful in the design of future clinical trials.
Subject(s)
Collagen Type VII/genetics , Collagen Type VII/metabolism , Muscular Diseases , Mutation/genetics , Statistics as Topic , Adolescent , Adult , Cells, Cultured , Child , Child, Preschool , Europe , Female , Fibroblasts/metabolism , Genetic Testing/methods , Glycine/genetics , Humans , Male , Muscle, Skeletal/metabolism , Muscular Diseases/genetics , Muscular Diseases/metabolism , Muscular Diseases/pathology , Phenotype , Young AdultABSTRACT
Array-CGH enables the detection of submicroscopic chromosomal deletions and duplications and leads to an accurate delineation of the imbalances, raising the possibility of genotype to phenotype and mapping minimal critical regions associated with particular patterns of clinical features. We report here on four patients sharing common clinical features (psychomotor retardation, coarse facies and ocular anomalies), with proximal 5q deletions identified by oligo array-CGH. The deletions range from 5.75 to 17.26-Mb in size and occurred de novo. A common 2.63-Mb region between the deletions described here can be defined in 5q12.1 (59,390,122-62,021,754 bp from 5pter, hg18) and includes 12 genes. Among them, KIF2A, which encodes a kinesin superfamily protein, is a particularly interesting candidate for the phenotype, as it suppresses the growth of axonal collateral branches and is involved in normal brain development. Ocular defects, albeit unspecific, seem to be common in the 5q12.1 deletion. Identification of additional cases of deletions involving the 5q12.1 region will allow more accurate genotype-phenotype correlations.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 5 , Eye Abnormalities/genetics , Intellectual Disability/genetics , Phenotype , Child , Child, Preschool , Comparative Genomic Hybridization , Female , Gene Order , Genetic Association Studies , Humans , MaleABSTRACT
Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.
Subject(s)
Chromosomes, Human, Pair 10/genetics , Hand Deformities, Congenital/genetics , Limb Deformities, Congenital/genetics , Segmental Duplications, Genomic/genetics , Adult , Child, Preschool , Comparative Genomic Hybridization/methods , F-Box Proteins/genetics , Female , Gene Rearrangement/genetics , Genetic Predisposition to Disease , Hand Deformities, Congenital/diagnostic imaging , Hand Deformities, Congenital/physiopathology , Humans , Infant , Limb Deformities, Congenital/diagnostic imaging , Limb Deformities, Congenital/physiopathology , Male , Pedigree , Phenotype , Proteasome Endopeptidase Complex/genetics , Proto-Oncogene Proteins/genetics , Radiography , Wnt Proteins/genetics , Young AdultABSTRACT
Overexpression of the C-type natriuretic peptide, encoded by the NPPC gene in 2q37.1, was recently reported in a patient presenting an overgrowth phenotype and a balanced t(2;7)(q37.1;q21.3) translocation. We present clinical, cytogenetic, and molecular data from two additional patients carrying balanced translocations involving the same 2q37.1 chromosome band and chromosomes 8 and 13, respectively. The clinical phenotype of these patients is very similar to the first patient described. In addition to the overgrowth syndrome, there is evidence of generalized cartilage dysplasia. In these two new cases, we found overexpression of NPPC, confirming that this unusual overgrowth phenotype in humans is due to the overexpression of this gene. The involvement of three different chromosomes and a cluster of breakpoints around the NPPC gene suggests that the overexpression of this gene in translocation patients could be due to its separation from a negative regulatory element located on chromosome 2, which would constitute a previously undescribed mutational mechanism.
Subject(s)
Chromosomes, Human, Pair 2/genetics , Growth Disorders/genetics , Natriuretic Peptide, C-Type/genetics , Translocation, Genetic , Child , Child, Preschool , Chromosome Breakage , Chromosomes, Human, Pair 7/genetics , Gene Expression Regulation , Growth Disorders/pathology , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Male , Phenotype , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Tubulinopathies are increasingly emerging major causes underlying complex cerebral malformations, particularly in case of microlissencephaly often associated with hypoplastic or absent corticospinal tracts. Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. We report on an early foetal case with FADS and microlissencephaly due to TUBB2B mutation. Neuropathological examination disclosed virtually absent cortical lamination, foci of neuronal overmigration into the leptomeningeal spaces, corpus callosum agenesis, cerebellar and brainstem hypoplasia and extremely severe hypoplasia of the spinal cord with no anterior and posterior horns and almost no motoneurons. At the cellular level, the p.Cys239Phe TUBB2B mutant leads to tubulin heterodimerization impairment, decreased ability to incorporate into the cytoskeleton, microtubule dynamics alteration, with an accelerated rate of depolymerization. To our knowledge, this is the first case of microlissencephaly to be reported presenting with a so severe and early form of FADS, highlighting the importance of tubulin mutation screening in the context of FADS with microlissencephaly.
Subject(s)
Arthrogryposis/genetics , Malformations of Cortical Development/genetics , Microcephaly/genetics , Tubulin/genetics , Adult , Arthrogryposis/physiopathology , Cerebellum/physiopathology , Female , Fetus , Humans , Malformations of Cortical Development/physiopathology , Microcephaly/physiopathology , Motor Neurons/pathology , Mutation , Spinal Cord/physiopathology , Tubulin/deficiencyABSTRACT
BACKGROUND: Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1 gene. The SMN2 copy number modulates the severity of SMA. The 0SMN1/1SMN2 genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. OBJECTIVE: The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. METHODS: SMA patients with the 0SMN1/1SMN2 genotype were retrospectively collected using the UMD-SMN1 France database. RESULTS: Data from 16 patients were reviewed. These 16 patients displayed type 0 SMA. At birth, a vast majority had profound hypotonia, severe muscle weakness, severe respiratory distress, and cranial nerves involvement (inability to suck/swallow, facial muscles weakness). They showed characteristics of fetal akinesia deformation sequence and congenital heart defects. Recurrent episodes of bradycardia were observed. Death occurred within the first month. At prenatal stage, decreased fetal movements were frequently reported, mostly only by mothers, in late stages of pregnancy; increased nuchal translucency was reported in about half of the cases; congenital heart defects, abnormal amniotic fluid volume, or joint contractures were occasionally reported. CONCLUSION: Despite a prenatal onset attested by severity at birth and signs of fetal akinesia deformation sequence, prenatal manifestations of type 0 SMA are not specific and not constant. As illustrated by the frequent association with congenital heart defects, type 0 SMA physiopathology is not restricted to motor neuron, highlighting that SMN function is critical for organogenesis.
Subject(s)
Arthrogryposis/physiopathology , Autonomic Nervous System Diseases/physiopathology , Cranial Nerve Diseases/physiopathology , Heart Defects, Congenital/physiopathology , Muscle Hypotonia/physiopathology , Respiratory Distress Syndrome, Newborn/physiopathology , Spinal Muscular Atrophies of Childhood/physiopathology , Arthrogryposis/etiology , Autonomic Nervous System Diseases/etiology , Cranial Nerve Diseases/etiology , Female , Genotype , Heart Defects, Congenital/diagnostic imaging , Heart Defects, Congenital/etiology , Homozygote , Humans , Infant, Newborn , Life Expectancy , Male , Muscle Hypotonia/etiology , Reflex, Abnormal , Respiratory Distress Syndrome, Newborn/etiology , Spinal Muscular Atrophies of Childhood/complications , Spinal Muscular Atrophies of Childhood/diagnostic imaging , Spinal Muscular Atrophies of Childhood/genetics , Survival of Motor Neuron 1 Protein/genetics , Survival of Motor Neuron 2 Protein/genetics , Ultrasonography, PrenatalABSTRACT
The increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novo overlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1B and the ENG genes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1 within the deletion, nail dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1B deletion, epistaxis and cutaneous-mucous telangiectasias explained by ENG haploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations.