ABSTRACT
The phenotypes associated with MED12 pathogenic variants are diverse. Male patients usually have missense variants, but the effects of base substitutions on mRNA splicing have not been investigated. Here, we report a Japanese brother with intellectual disability, characteristic facial appearance with blepharophimosis, cleft palate, Fallot tetralogy, vesicoureteral reflux, and deafness. A known missense pathogenic variant was detected in MED12, NM_005120.3:c.887G>A p.(Arg296Gln), and X-linked Ohdo syndrome was diagnosed in combination with their phenotype. mRNA splicing of MED12 was evaluated qualitatively and quantitatively using long-range PCR-based targeted RNA sequencing (reverse transcribed long amplicon sequencing), and it was shown that this missense variant simultaneously causes aberrant splicing of the 42-bp in-frame deletion in exon 7, r.847_888del, which accounts for approximately 30% of the mRNAs in both siblings. The X chromosome inactivation study showed that the X chromosome carrying the mutant allele was 100% inactivated in the carrier mothers. mRNA level analysis is essential for the accurate interpretation of the effects of variants. In this case, the MED12 protein function may be reduced by more than just an amino acid substitution, resulting in the patients with the most severe phenotype of MED12-related syndrome in males.
Subject(s)
Blepharophimosis , Mediator Complex , RNA Splicing , Child , Female , Humans , Male , Abnormalities, Multiple , Blepharophimosis/genetics , Blepharophimosis/pathology , Blepharoptosis , Cleft Palate/genetics , Cleft Palate/pathology , Deafness/genetics , Deafness/pathology , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/pathology , Heart Defects, Congenital , Intellectual Disability/genetics , Intellectual Disability/pathology , Mediator Complex/genetics , Mutation, Missense , Pedigree , Phenotype , RNA Splicing/genetics , Vesico-Ureteral Reflux/genetics , Vesico-Ureteral Reflux/pathology , X Chromosome Inactivation/geneticsABSTRACT
Van den Ende-Gupta syndrome (VDEGS) (MIM#600920) is characterized by skeletal and craniofacial abnormalities that include prominent ears, downslanting palpebral fissures, blepharophimosis, hypoplastic maxilla with or without a cleft palate, a narrow and convex nasal bridge and an everted lower lip, camptodactyly and arachnodactyly. Intelligence is normal. Recent studies have reported that patients with VDEGS have pathogenic variants in the SCARF2 gene on chromosome 22q11.21. Here, we report two Turkish patients with two novel variants [c.2291_2292insC (p.Ser765LeufsTer6) and c.488G>A (p.Cys63Tyr)] in the SCARF2 gene. In silico analysis predicted that both of these novel variants were pathogenic. To the best of our knowledge, this is the first case report of this syndrome in Turkey.
Subject(s)
Abnormalities, Multiple , Arachnodactyly , Blepharophimosis , Cleft Lip , Cleft Palate , Contracture , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Arachnodactyly/genetics , Blepharophimosis/genetics , Blepharophimosis/pathology , Cleft Lip/diagnosis , Cleft Lip/genetics , Cleft Palate/diagnosis , Cleft Palate/genetics , Contracture/genetics , HumansABSTRACT
MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.
Subject(s)
Abnormalities, Multiple/genetics , Agenesis of Corpus Callosum/genetics , Anus, Imperforate/genetics , Blepharophimosis/genetics , Blepharoptosis/genetics , Cholestasis/genetics , Cleft Palate/genetics , Constipation/genetics , Craniofacial Abnormalities/genetics , Heart Defects, Congenital/genetics , Intellectual Disability/genetics , Marfan Syndrome/genetics , Mediator Complex/genetics , Mental Retardation, X-Linked/genetics , Muscle Hypotonia/congenital , Retinitis Pigmentosa/genetics , Abnormalities, Multiple/pathology , Agenesis of Corpus Callosum/pathology , Anus, Imperforate/pathology , Blepharophimosis/pathology , Blepharoptosis/pathology , Cholestasis/pathology , Cleft Palate/pathology , Constipation/pathology , Craniofacial Abnormalities/pathology , Heart Defects, Congenital/pathology , Humans , Intellectual Disability/pathology , Marfan Syndrome/pathology , Mental Retardation, X-Linked/pathology , Muscle Hypotonia/genetics , Muscle Hypotonia/pathology , Phenotype , Retinitis Pigmentosa/pathologyABSTRACT
Van den Ende-Gupta syndrome (VDEGS) is a rare autosomal recessive condition characterized by distinctive facial and skeletal features, and in most affected persons, by biallelic pathogenic variants in SCARF2. We review the type and frequency of the clinical features in 36 reported individuals with features of VDEGS, 15 (42%) of whom had known pathogenic variants in SCARF2, 6 (16%) with negative SCARF2 testing, and 15 (42%) not tested. We also report three new individuals with pathogenic variants in SCARF2 and clinical features of VDEGS. Of the six persons without known pathogenic variants in SCARF2, three remain unsolved despite extensive genetic testing. Three were found to have pathogenic ABL1 variants using whole exome sequencing (WES) or whole genome sequencing (WGS). Their phenotype was consistent with the congenital heart disease and skeletal malformations syndrome (CHDSKM), which has been associated with ABL1 variants. Of the three unsolved cases, two were brothers who underwent WGS and targeted long-range sequencing of both SCARF2 and ABL1, and the third person who underwent WES and RNA sequencing for SCARF2. Because these affected individuals with classical features of VDEGS lacked a detectable pathogenic SCARF2 variant, genetic heterogeneity is likely. Our study shows the importance of performing genetic testing on individuals with the VDEGS "phenotype," either as a targeted gene analysis (SCARF2, ABL1) or WES/WGS. Additionally, individuals with the combination of arachnodactyly and blepharophimosis should undergo echocardiography while awaiting results of molecular testing due to the overlapping physical features of VDEGS and CHDSKM.
Subject(s)
Abnormalities, Multiple/genetics , Arachnodactyly/genetics , Blepharophimosis/genetics , Contracture/genetics , Heart Defects, Congenital/genetics , Proto-Oncogene Proteins c-abl/genetics , Scavenger Receptors, Class F/genetics , Abnormalities, Multiple/pathology , Adolescent , Adult , Arachnodactyly/pathology , Blepharophimosis/pathology , Child , Child, Preschool , Contracture/pathology , Female , Genes, Recessive/genetics , Genetic Heterogeneity , Genetic Predisposition to Disease , Heart Defects, Congenital/pathology , Humans , Infant , Male , Middle Aged , Exome Sequencing , Young AdultABSTRACT
3MC syndrome is a rare condition manifesting with typical facial appearance, postnatal growth deficiency, skeletal manifestations, and genitourinary tract anomalies. 3MC is caused by biallelic pathogenic variants in MASP1, COLEC11, or COLEC10. Here, we report an affected subject of Kurdish origin from Turkey presenting with facial dysmorphisms, such as, hypertelorism, blepharophimosis, blepharoptosis, highly arched eyebrows, umbilical hernia, and caudal appendage. These features were compatible with 3MC syndrome. Molecular analysis revealed a novel homozygous pathogenic variant, c.310C > T; p.Gln104Ter in the MASP1 gene, resulting in a premature stop codon. Few subjects with 3MC syndrome have been reported in the literature so far. Thus, detailed study of this subject contributes to the evolving clinical and genetic characterization of 3MC syndrome.
Subject(s)
Abnormalities, Multiple/genetics , Collectins/genetics , Craniofacial Abnormalities/genetics , Mannose-Binding Protein-Associated Serine Proteases/genetics , Muscular Atrophy/genetics , Abnormalities, Multiple/pathology , Blepharophimosis/genetics , Blepharophimosis/pathology , Blepharoptosis/genetics , Blepharoptosis/pathology , Cleft Lip/genetics , Cleft Lip/pathology , Cleft Palate/genetics , Cleft Palate/pathology , Craniofacial Abnormalities/pathology , Craniosynostoses/genetics , Craniosynostoses/pathology , Eye Abnormalities/genetics , Eye Abnormalities/pathology , Humans , Hypertelorism/genetics , Hypertelorism/pathology , Infant , Male , Muscular Atrophy/pathology , Turkey/epidemiologyABSTRACT
CDK9 has been considered a candidate gene involved in the CHARGE-like syndrome in a pair of cousins. We report an 8-year-old boy with a strikingly similar phenotype including facial asymmetry, microtia with preauricular tags and bilateral hearing loss, cleft lip and palate, cardiac dysrhythmia, and undescended testes. Joint contracture, no finger flexion creases, and large halluces were the same as those of a previously reported patient with homozygous CDK9 variants. The ocular phenotype included blepharophimosis, lacrimal duct obstruction, eyelid dermoids, Duane syndrome-like abduction deficit, and congenital cataracts. Optical coherence tomography and electroretinography evaluations revealed severe retinal dystrophy had developed at an early age. Trio-based whole-exome sequencing identified compound heterozygous variants in CDK9 [p.(A288T) of maternal origin and p.(R303C) of paternal origin] in the patient. Variants' kinase activities were reduced compared with wild type. We concluded that CDK9 biallelic variants cause a CHARGE-like malformation syndrome with retinal dystrophy as a distinguishing feature.
Subject(s)
Blepharophimosis/genetics , CHARGE Syndrome/genetics , Cyclin-Dependent Kinase 9/genetics , Retinal Dystrophies/genetics , Alleles , Blepharophimosis/diagnosis , Blepharophimosis/pathology , CHARGE Syndrome/diagnosis , CHARGE Syndrome/diagnostic imaging , CHARGE Syndrome/pathology , Child , Cleft Lip/diagnostic imaging , Cleft Lip/genetics , Cleft Lip/pathology , Cleft Palate/diagnostic imaging , Cleft Palate/genetics , Cleft Palate/pathology , Electroretinography , Homozygote , Humans , Lacrimal Duct Obstruction/diagnosis , Lacrimal Duct Obstruction/genetics , Lacrimal Duct Obstruction/pathology , Male , Mutation/genetics , Pedigree , Phenotype , Retinal Dystrophies/diagnosis , Retinal Dystrophies/diagnostic imaging , Retinal Dystrophies/pathology , Tomography, Optical Coherence , Exome SequencingABSTRACT
Blepharophimosis-ptosis-intellectual disability syndrome (BPID) is an extremely rare recognizable blepharophimosis intellectual disability syndrome (BID). It is caused by biallelic variants in the UBE3B gene with only 24 patients described worldwide. Herein, we report on the clinical, brain imaging and molecular findings of additional nine patients from six unrelated Egyptian families. Patients presented with the characteristic features of the syndrome including blepharophimosis, ptosis, upslanted palpebral fissures with epicanthic folds, hypertelorism, long philtrum, high arched palate, micrognathia, microcephaly, and intellectual disability. Other findings were congenital heart disease (5 patients), talipes equinovarus (5 patients), genital anomalies (5 patients), autistic features (4 patients), cleft palate (2 patients), hearing loss (2 patients), and renal anomalies (1 patient). New or rarely reported findings were spherophakia, subvalvular aortic stenosis and hypoplastic nails, and terminal phalanges. Brain MRI, performed for 7 patients, showed hypogenesis or almost complete agenesis of corpus callosum. Genetic studies revealed five novel homozygous UBE3B variants. Of them, the c.1076G>A (p.W359*) was found in three patients from two unrelated families who shared similar haplotype suggesting a likely founder effect. Our results strengthen the clinical, dysmorphic, and brain imaging characteristic of this unique type of BID and extend the mutational spectrum associated with the disorder.
Subject(s)
Blepharophimosis/genetics , Homozygote , Intellectual Disability/genetics , Mutation , Phenotype , Skin Abnormalities/genetics , Ubiquitin-Protein Ligases/genetics , Urogenital Abnormalities/genetics , Blepharophimosis/pathology , Child , Child, Preschool , Egypt , Female , Humans , Infant , Infant, Newborn , Intellectual Disability/pathology , Male , Pedigree , Skin Abnormalities/pathology , Urogenital Abnormalities/pathologySubject(s)
Blepharophimosis/genetics , Congenital Hypothyroidism/genetics , Exome Sequencing , Frameshift Mutation , Heart Defects, Congenital/genetics , Histone Acetyltransferases/genetics , Intellectual Disability/genetics , Joint Instability/genetics , Blepharophimosis/pathology , Congenital Hypothyroidism/pathology , Facies , Heart Defects, Congenital/pathology , Humans , Infant, Newborn , Intellectual Disability/pathology , Joint Instability/pathology , MaleSubject(s)
Abnormalities, Multiple/etiology , Blepharophimosis/etiology , Blepharoptosis/etiology , Chromosomes, Human, X/genetics , Genetic Diseases, X-Linked/etiology , Heart Defects, Congenital/etiology , Intellectual Disability/etiology , Mediator Complex/genetics , Mutation , Abnormalities, Multiple/pathology , Blepharophimosis/pathology , Blepharoptosis/pathology , Child, Preschool , Female , Genetic Diseases, X-Linked/pathology , Heart Defects, Congenital/pathology , Humans , Intellectual Disability/pathology , PrognosisABSTRACT
BACKGROUND: Blepharophimosis syndrome (BPES) is characterized by eyelid malformation with occasional premature ovarian failure. Mutations in FOXL2 underlie a fraction of BPES cases. OBJECTIVE: We aimed to investigate the genetic basis of BPES in 26 Chinese families that included 78 patients. METHODS: We performed ophthalmological examinations on each family member. We used Sanger sequencing to screen FOXL2 exons and their flanking sequences. We also performed bioinformatics studies, structural modeling and pathogenicity evaluations on all identified variations. Literature was reviewed and genotype-phenotype correlation analysis was performed. RESULTS: The patients had typical manifestations of BPES. Ten mutations were identified in ten of the twenty-six families. Among these, seven were novel mutations. These included the six truncating mutations, p.Glu69*, p.Gly256Glyfs*14, p.Ala14Serfs*135, p.Pro333Profs*200, p.Pro290Leufs*70, and p.Pro157Profs*91, and one missense mutation, p.Tyr59Cys. The mutations were scattered within the gene, and no mutational hotspots were found. Genotype-phenotype correlation analysis showed that frameshift or nonsense mutations were correlated with type I BPES, while in-frame or missense mutations were associated with type II BPES. CONCLUSION: We report the largest BPES cohort in China thus far as well as seven novel mutations in FOXL2. The identification of novel mutations has not only expanded the mutational spectrum of the gene (which is valuable for mutation detection-based screening) but also suggests that most mutations within the Chinese population may not have been characterized yet.
Subject(s)
Blepharophimosis/genetics , Family , Forkhead Box Protein L2/genetics , Mutation, Missense , Pedigree , Adult , Amino Acid Substitution , Blepharophimosis/pathology , Child , Child, Preschool , China , Female , Humans , Infant , MaleABSTRACT
BACKGROUND/AIMS: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease caused by FOXL2 gene mutations, and it is clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). Functional study of novel mutations is especially critical for female patients, as it may allow the prediction of infertility and early planning of an appropriate therapy. METHODS: A clinical and molecular genetic investigation was performed in all members of a Chinese family with BPES. Genomic DNA was extracted, and the FOXL2 coding region was sequenced. Subcellular localization was performed by confocal microscopy. Transactivation studies were performed by real-time PCR, dual luciferase reporter assays and electrophoretic mobility shift assays. RESULTS: A novel deletion mutation (C.634_641 del, CCCATGC) between the forkhead domain and the polyalanine domain was found, resulting in a frameshift mutation and a truncated protein. Functional studies showed a strong cytoplasmic mislocalization and abnormal transactivation activity, implying a type I kind mutation with a large chance of infertility. CONCLUSION: This study identifies that this mutation indicates the probability of developing into POF and shows the importance and necessity of early recognition of BPES type through mutation testing for female patients. Prompt personalized therapy and follow-up is of great clinical significance for female patients carrying this kind of mutation.
Subject(s)
Blepharophimosis/genetics , Forkhead Box Protein L2/genetics , Skin Abnormalities/genetics , Urogenital Abnormalities/genetics , Base Sequence , Blepharophimosis/pathology , Child , Cytoplasm/metabolism , DNA/chemistry , DNA/isolation & purification , DNA/metabolism , Electrophoretic Mobility Shift Assay , Female , Forkhead Box Protein L2/metabolism , Frameshift Mutation , Humans , Male , Microscopy, Confocal , Pedigree , Sequence Analysis, DNA , Sequence Deletion , Skin Abnormalities/pathology , Transcriptional Activation , Urogenital Abnormalities/pathologyABSTRACT
Interstitial deletions of the short and long arms of chromosome 5 are rare cytogenetic abnormalities. The 5p distal deletion is a genetic disorder characterized by a high-pitched cat-like cry, microcephaly, epicanthal folds, micrognathia, severe intellectual disability and motor delays. Previously, more than 46 patients with the 5q deletion have been reported. Here, we report de novo interstitial deletions involving 5p14.1-p15.2 and 5q14.3-q23.2 in a patient with multiple congenital abnormalities, including blepharophimosis, arthrogryposis, short neck, round face, pelvic kidney, agenesis of the corpus callosum, and clubfoot. The deletions were characterized using GTG banding and aCGH microarray analysis. Concurrent 5p and 5q interstitial deletions in humans have not been previously reported. We also discussed the relationship between the 5q deleted region and clubfeet.
Subject(s)
Arthrogryposis/genetics , Blepharophimosis/genetics , Chromosome Deletion , Chromosomes, Human, Pair 5 , Clubfoot/genetics , Congenital Abnormalities/genetics , Adult , Arthrogryposis/complications , Arthrogryposis/pathology , Blepharophimosis/complications , Blepharophimosis/pathology , Child, Preschool , Clubfoot/complications , Clubfoot/pathology , Congenital Abnormalities/pathology , Female , Humans , Infant , Male , PrognosisABSTRACT
Mutations in KAT6B gene are responsible for Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and genitopatellar syndrome (GPS), with most mutations occurring in exon 18. A 4-year-old Chinese boy presented with short stature but no other clinical features of SBBYSS or GPS had a de novo novel nonsense pathogenic mutation in exon 14 of the KAT6B gene at position c.2636T>A (p.Leu879X). The correlation analysis of genotype-phenotype indicated distinctive clinical features (short stature, growth hormone deficiency, and delayed bone age) compared with the classical mutations of KAT6B gene. To the best of our knowledge, this is the first report of KAT6B gene mutation in any Chinese individual. This work expands the mutant phenotypic spectrum of the KAT6B gene.
Subject(s)
Abnormalities, Multiple/pathology , Blepharophimosis/genetics , Blepharophimosis/pathology , Congenital Hypothyroidism/genetics , Congenital Hypothyroidism/pathology , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/pathology , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology , Histone Acetyltransferases/genetics , Intellectual Disability/genetics , Intellectual Disability/pathology , Joint Instability/genetics , Joint Instability/pathology , Kidney/abnormalities , Mutation/genetics , Patella/abnormalities , Psychomotor Disorders/genetics , Psychomotor Disorders/pathology , Scrotum/abnormalities , Urogenital Abnormalities/genetics , Urogenital Abnormalities/pathology , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Blepharophimosis/diagnosis , Child, Preschool , Codon, Nonsense/genetics , Congenital Hypothyroidism/diagnosis , Craniofacial Abnormalities/diagnosis , Exons/genetics , Facies , Heart Defects, Congenital/diagnosis , Humans , Intellectual Disability/diagnosis , Joint Instability/diagnosis , Kidney/pathology , Male , Patella/pathology , Phenotype , Psychomotor Disorders/diagnosis , Scrotum/pathology , Urogenital Abnormalities/diagnosisABSTRACT
In a 46 XY individual, the presence of the Y chromosome harboring the testis-determining factor (SRY) triggers testis determination and differentiation. In a 46 XX individual, the absence of SRY and the activation of genes associated with the female pathway lead to ovarian development. The latter process has long been considered as a default pathway. However, recent studies have cast doubts on this dogma. Here, after a brief overview of the main steps of ovarian development, we focus on three genes WNT4, RSPO1 and FOXL2 that are essential for ovarian determination, differentiation and/or maintenance. Special attention is paid to FOXL2 whose mutations are responsible for the blepharophimosis syndrome, often associated with female infertility, and for cancer. We highlight the cooperation of WNT4, RSPO1 and FOXL2 within a regulatory network and the need for further research to better understand their role in defining and maintaining ovarian identity.
Subject(s)
Forkhead Transcription Factors/genetics , Ovary/growth & development , Thrombospondins/genetics , Wnt4 Protein/genetics , Blepharophimosis/genetics , Blepharophimosis/pathology , Female , Forkhead Box Protein L2 , Gene Regulatory Networks/genetics , Humans , Infertility, Female/genetics , Infertility, Female/pathology , Male , Ovary/metabolism , Sex-Determining Region Y Protein/genetics , Skin Abnormalities/genetics , Skin Abnormalities/pathology , Urogenital Abnormalities/genetics , Urogenital Abnormalities/pathologyABSTRACT
Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and genitopatellar syndrome (GTPTS) are clinically similar disorders with some overlapping features. Although they are currently considered to be distinct clinical entities, both were found to be caused by de novo truncating sequence variants in the KAT6B (lysine acetyltransferase 6B) gene, strongly suggesting that they are allelic disorders. Herein, we report the clinical and genetic findings in a girl presenting with a serious multiple congenital anomaly syndrome with phenotypic features overlapping both SBBYSS and GTPTS; pointing out that the clinical distinction between these disorders is not exact and there do exist patients, in whom conventional clinical classification is problematic. Genetic analyses revealed a truncating c.4592delA (p.Asn1531Thrfs*18) variant in the last KAT6B exon. Our findings support that phenotypes associated with typical KAT6B disease-causing variants should be referred to as 'KAT6B spectrum disorders' or 'KAT6B related disorders', rather than their current SBBYSS and GTPTS classification.
Subject(s)
Abnormalities, Multiple/diagnosis , Blepharophimosis/diagnosis , Congenital Hypothyroidism/diagnosis , Craniofacial Abnormalities/diagnosis , Heart Defects, Congenital/diagnosis , Histone Acetyltransferases/genetics , Intellectual Disability/diagnosis , Joint Instability/diagnosis , Kidney/abnormalities , Patella/abnormalities , Psychomotor Disorders/diagnosis , Scrotum/abnormalities , Urogenital Abnormalities/diagnosis , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Blepharophimosis/genetics , Blepharophimosis/pathology , Child, Preschool , Congenital Hypothyroidism/genetics , Congenital Hypothyroidism/pathology , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/pathology , Exons , Facies , Female , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology , Humans , Intellectual Disability/genetics , Intellectual Disability/pathology , Joint Instability/genetics , Joint Instability/pathology , Kidney/pathology , Mutation , Patella/pathology , Phenotype , Psychomotor Disorders/genetics , Psychomotor Disorders/pathology , Scrotum/pathology , Urogenital Abnormalities/genetics , Urogenital Abnormalities/pathologyABSTRACT
One to two percent of all children are born with a developmental disorder requiring pediatric hospital admissions. For many such syndromes, the molecular pathogenesis remains poorly characterized. Parallel developmental disorders in other species could provide complementary models for human rare diseases by uncovering new candidate genes, improving the understanding of the molecular mechanisms and opening possibilities for therapeutic trials. We performed various experiments, e.g. combined genome-wide association and next generation sequencing, to investigate the clinico-pathological features and genetic causes of three developmental syndromes in dogs, including craniomandibular osteopathy (CMO), a previously undescribed skeletal syndrome, and dental hypomineralization, for which we identified pathogenic variants in the canine SLC37A2 (truncating splicing enhancer variant), SCARF2 (truncating 2-bp deletion) and FAM20C (missense variant) genes, respectively. CMO is a clinical equivalent to an infantile cortical hyperostosis (Caffey disease), for which SLC37A2 is a new candidate gene. SLC37A2 is a poorly characterized member of a glucose-phosphate transporter family without previous disease associations. It is expressed in many tissues, including cells of the macrophage lineage, e.g. osteoclasts, and suggests a disease mechanism, in which an impaired glucose homeostasis in osteoclasts compromises their function in the developing bone, leading to hyperostosis. Mutations in SCARF2 and FAM20C have been associated with the human van den Ende-Gupta and Raine syndromes that include numerous features similar to the affected dogs. Given the growing interest in the molecular characterization and treatment of human rare diseases, our study presents three novel physiologically relevant models for further research and therapy approaches, while providing the molecular identity for the canine conditions.
Subject(s)
Abnormalities, Multiple/genetics , Arachnodactyly/genetics , Blepharophimosis/genetics , Cleft Palate/genetics , Contracture/genetics , Exophthalmos/genetics , Hyperostosis, Cortical, Congenital/genetics , Microcephaly/genetics , Osteosclerosis/genetics , Abnormalities, Multiple/pathology , Animals , Antiporters/genetics , Arachnodactyly/pathology , Blepharophimosis/pathology , Bone Diseases/genetics , Bone Diseases/pathology , Casein Kinase I/genetics , Cleft Palate/pathology , Contracture/pathology , Craniomandibular Disorders/genetics , Craniomandibular Disorders/pathology , Disease Models, Animal , Dogs , Exophthalmos/pathology , Extracellular Matrix Proteins/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Hyperostosis, Cortical, Congenital/pathology , Microcephaly/pathology , Osteosclerosis/pathology , Scavenger Receptors, Class F/geneticsABSTRACT
BACKGROUND: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease. Mutations in the forkhead box L2 (FOXL2) gene cause two types of BPES distinguished by the presence (type I) and absence (type II) of premature ovarian failure (POF). The purpose of this study was to identify possible mutations in FOXL2 in two Chinese families with BPES. METHODS: Two large autosomal dominant Chinese BPES families were enrolled in this study. Genomic DNA was obtained from the leukocytes in peripheral venous blood. Four overlapping sets of primers were used to amplify the entire coding region and nearby intron sequences of the FOXL2 gene for mutations detection using polymerase chain reaction (PCR) and sequencing analyses. The sequencing results were analyzed using DNAstar software. RESULTS: All patients of the two families demonstrated typical features of BPES type II, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus without female infertility (POF). A novel FOXL2 heterozygous indel mutation c.675_690delinsT, including a 16-bp deletion and a 1-bp(T) insertion (p.Ala226_Ala230del), which would result in deletion of 5 alanine residues of a poly-alanine (poly-Ala) tract in the protein, was identified in all affected members of family A. A novel heterozygous missense mutation (c.223C > T, p.Leu75Phe) was identified in family B. CONCLUSIONS: Two novel FOXL2 mutations were identified in Chinese families with BPES. Our results expand the spectrum of FOXL2 mutations and provide additional structure-function insights into the FOXL2 protein.
Subject(s)
Blepharophimosis/genetics , Forkhead Transcription Factors/genetics , Mutation/genetics , Skin Abnormalities/genetics , Base Sequence , Blepharophimosis/pathology , DNA Primers/genetics , Female , Forkhead Box Protein L2 , Genes, Dominant/genetics , Humans , Molecular Sequence Data , Pedigree , Sequence Analysis, DNA , Skin Abnormalities/pathology , Urogenital AbnormalitiesABSTRACT
Intellectual disability (ID) is estimated to affect 1-3% of the general population and is a common reason for referrals to pediatric and adult geneticists, as well as neurologists. There are many genetic and non-genetic causes of ID; X-linked forms are identifiable through their characteristic inheritance pattern. Current testing methods have been able to identify over 100 genes on the X chromosome responsible for X-linked intellectual disability (XLID) syndromes. MED12 [MIM *300188] (mediator complex subunit 12) mutations have been linked to numerous XLID syndromes, including Lujan, FG, and Ohdo, and MED12 is included in many XLID panels. MED12 is located at Xq13.1 and its product has roles in transcriptional activation and repression. We describe two affected male siblings and their unaffected mother with a novel missense mutation in MED12, c.4147G>A (p.Ala1383Thr). The siblings share some features of Ohdo syndrome, including feeding difficulties, microcephaly, and speech delay. However, additional attributes such as hypertonia, eosinophilic esophagitis, penile chordee, and particular facial dysmorphisms depart sufficiently from individuals previously described such that they appear to represent a new and expanded phenotype. This case lends credence to the evolving theory that the subtypes of Ohdo, and perhaps other MED12 disorders, reflect a spectrum of characteristics, rather than distinct syndromes. As XLID panel testing and whole exome sequencing (WES) becomes a standard of care for affected males, further MED12 mutations will broaden the phenotype of these intriguing disorders and challenge clinicians to rethink the current diagnostic boundaries.
Subject(s)
Abnormalities, Multiple/genetics , Blepharophimosis/genetics , Blepharoptosis/genetics , Craniofacial Abnormalities/genetics , Eosinophilic Esophagitis/genetics , Genes, X-Linked/genetics , Heart Defects, Congenital/genetics , Intellectual Disability/genetics , Mediator Complex/genetics , Muscle Hypertonia/genetics , Muscular Atrophy/genetics , Mutation, Missense/genetics , Abnormalities, Multiple/pathology , Adult , Blepharophimosis/pathology , Blepharoptosis/pathology , Child , Craniofacial Abnormalities/pathology , Eosinophilic Esophagitis/pathology , Heart Defects, Congenital/pathology , Humans , Infant , Intellectual Disability/pathology , Male , Muscle Hypertonia/pathology , Muscular Atrophy/pathology , Phenotype , PrognosisSubject(s)
Abnormalities, Multiple/genetics , Blepharophimosis/genetics , Craniofacial Abnormalities/genetics , DNA Copy Number Variations , Monosomy , Phenotype , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/pathology , Adolescent , Blepharophimosis/diagnosis , Blepharophimosis/pathology , Child, Preschool , Chromosomes, Human, Pair 8 , Craniofacial Abnormalities/diagnosis , Craniofacial Abnormalities/pathology , Facies , Female , Genotype , Heterozygote , Humans , Male , Oligonucleotide Array Sequence AnalysisABSTRACT
KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.