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Development ; 148(16)2021 08 15.
Article En | MEDLINE | ID: mdl-34351428

Neocortical progenitor cells generate subtypes of excitatory projection neurons in sequential order followed by the generation of astrocytes. The transcription factor zinc finger and BTB domain-containing protein 20 (ZBTB20) has been implicated in regulation of cell specification during neocortical development. Here, we show that ZBTB20 instructs the generation of a subset of callosal projections neurons in cortical layers II/III in mouse. Conditional deletion of Zbtb20 in cortical progenitors, and to a lesser degree in differentiating neurons, leads to an increase in the number of layer IV neurons at the expense of layer II/III neurons. Astrogliogenesis is also affected in the mutants with an increase in the number of a specific subset of astrocytes expressing GFAP. Astrogliogenesis is more severely disrupted by a ZBTB20 protein containing dominant mutations linked to Primrose syndrome, suggesting that ZBTB20 acts in concert with other ZBTB proteins that were also affected by the dominant-negative protein to instruct astrogliogenesis. Overall, our data suggest that ZBTB20 acts both in progenitors and in postmitotic cells to regulate cell fate specification in the mammalian neocortex.

Astrocytes/metabolism , Neocortex/growth & development , Neurogenesis/genetics , Neurons/metabolism , Transcription Factors/metabolism , Abnormalities, Multiple/genetics , Animals , Calcinosis/genetics , Ear Diseases/genetics , Female , Gene Knockout Techniques , Intellectual Disability/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscular Atrophy/genetics , Mutation, Missense , Neocortex/metabolism , Signal Transduction/genetics , Stem Cells/metabolism , Transcription Factors/genetics
J Appl Genet ; 62(1): 107-113, 2021 Feb.
Article En | MEDLINE | ID: mdl-33131036

Auriculocondylar syndrome (ACS) is an ultra-rare disorder that arises from developmental defects of the first and second pharyngeal arches. Three subtypes of ACS have been described so far, i.e., ACS1 (MIM: 602483), ACS2 (MIM: 600810), and ACS3 (MIM: 131240). The majority of patients, however, are affected by ACS2, which results from the mutations in the PLCB4 gene. Herein, we have described an 8-year-old male patient presenting with ACS2 and summarized the molecular and phenotypic spectrum of the syndrome. We have also compared the clinical features of our case to three other previously described cases (one sporadic and two familial) harboring the same heterozygous missense variant c.1862G>A, p.Arg621His in the PLCB4 gene. The mutation was detected using whole-exome sequencing (WES). Due to low coverage of WES and suspicion of somatic mosaicism, the variant was additionally reassessed by deep targeted next-generation sequencing panel of genes related to the craniofacial disorders, and next confirmed by Sanger sequencing. ACS2 presents high intra- and interfamilial phenotypic heterogeneity that impedes reaching an exact clinical and molecular diagnosis. Thus, describing additional cases, carrying even the known mutation, but resulting in variable phenotypes, is essential for better understanding of such orphan Mendelian diseases.

Ear Diseases/genetics , Ear/abnormalities , Child , Humans , Male , Mutation , Pedigree , Phenotype , Phospholipase C beta/genetics
Eur J Med Genet ; 63(8): 103967, 2020 Aug.
Article En | MEDLINE | ID: mdl-32473227

Primrose syndrome (OMIM 259050) is a rare disorder characterised by macrocephaly with developmental delay, a recognisable facial phenotype, altered glucose metabolism, and other features such as sensorineural hearing loss, short stature, and calcification of the ear cartilage. It is caused by heterozygous variants in ZBTB20, a member of the POK family of transcription repressors. Recently, this gene was shown to have a role in skeletal development through its action on chondrocyte differentiation by repression of SOX9. We describe five unrelated patients with Primrose syndrome and distinct skeletal features including multiple Wormian bones, platybasia, bitemporal bossing, bathrocephaly, slender bones, epiphyseal and spondylar dysplasia. The radiological abnormalities of the skull and the epiphyseal dysplasia were the most consistent findings. This novel constellation of skeletal features expands the phenotypic spectrum of the disorder.

Abnormalities, Multiple/pathology , Bone and Bones/abnormalities , Calcinosis/pathology , Ear Diseases/pathology , Intellectual Disability/pathology , Muscular Atrophy/pathology , Phenotype , Abnormalities, Multiple/genetics , Adolescent , Bone and Bones/diagnostic imaging , Calcinosis/genetics , Child , Child, Preschool , Ear Diseases/genetics , Female , Humans , Intellectual Disability/genetics , Male , Muscular Atrophy/genetics , Nerve Tissue Proteins/genetics , SOXB1 Transcription Factors/genetics , Transcription Factors/genetics , Young Adult
Clin Genet ; 97(6): 890-901, 2020 06.
Article En | MEDLINE | ID: mdl-32266967

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.

Abnormalities, Multiple/genetics , Calcinosis/genetics , Ear Diseases/genetics , Genetic Predisposition to Disease , Intellectual Disability/genetics , Megalencephaly/genetics , Muscular Atrophy/genetics , Nerve Tissue Proteins/genetics , Transcription Factors/genetics , 3-Hydroxyacyl CoA Dehydrogenases/genetics , Abnormalities, Multiple/pathology , Acetyl-CoA C-Acyltransferase/genetics , Adolescent , Adult , Calcinosis/pathology , Carbon-Carbon Double Bond Isomerases/genetics , Child , Child, Preschool , Ear Diseases/pathology , Enoyl-CoA Hydratase/genetics , Face/abnormalities , Female , Genetic Association Studies , Heterozygote , Humans , Infant , Intellectual Disability/pathology , Male , Megalencephaly/pathology , Middle Aged , Mitochondria/genetics , Mitochondria/pathology , Muscular Atrophy/pathology , Mutation , Mutation, Missense/genetics , Phenotype , Racemases and Epimerases/genetics , Testicular Neoplasms , Young Adult
Am J Med Genet A ; 182(5): 1104-1116, 2020 05.
Article En | MEDLINE | ID: mdl-32133772

Craniofacial morphogenesis is regulated in part by signaling from the Endothelin receptor type A (EDNRA). Pathogenic variants in EDNRA signaling pathway components EDNRA, GNAI3, PCLB4, and EDN1 cause Mandibulofacial Dysostosis with Alopecia (MFDA), Auriculocondylar syndrome (ARCND) 1, 2, and 3, respectively. However, cardiovascular development is normal in MFDA and ARCND individuals, unlike Ednra knockout mice. One explanation may be that partial EDNRA signaling remains in MFDA and ARCND, as mice with reduced, but not absent, EDNRA signaling also lack a cardiovascular phenotype. Here we report an individual with craniofacial and cardiovascular malformations mimicking the Ednra -/- mouse phenotype, including a distinctive micrognathia with microstomia and a hypoplastic aortic arch. Exome sequencing found a novel homozygous missense variant in EDNRA (c.1142A>C; p.Q381P). Bioluminescence resonance energy transfer assays revealed that this amino acid substitution in helix 8 of EDNRA prevents recruitment of G proteins to the receptor, abrogating subsequent receptor activation by its ligand, Endothelin-1. This homozygous variant is thus the first reported loss-of-function EDNRA allele, resulting in a syndrome we have named Oro-Oto-Cardiac Syndrome. Further, our results illustrate that EDNRA signaling is required for both normal human craniofacial and cardiovascular development, and that limited EDNRA signaling is likely retained in ARCND and MFDA individuals. This work illustrates a straightforward approach to identifying the functional consequence of novel genetic variants in signaling molecules associated with malformation syndromes.

Craniofacial Abnormalities/genetics , Ear Diseases/genetics , Ear/abnormalities , Genetic Predisposition to Disease , Mandibulofacial Dysostosis/genetics , Receptor, Endothelin A/genetics , Animals , Craniofacial Abnormalities/physiopathology , Ear/physiopathology , Ear Diseases/physiopathology , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Gene Expression Regulation, Developmental/genetics , Humans , Loss of Function Mutation/genetics , Mandibulofacial Dysostosis/physiopathology , Mice , Mice, Knockout , Morphogenesis/genetics , Neural Crest/growth & development , Neural Crest/pathology , Phenotype , Signal Transduction/genetics
Eur J Med Genet ; 63(6): 103917, 2020 Jun.
Article En | MEDLINE | ID: mdl-32201334

Auriculocondylar syndrome (ARCND, MIM #614669, #602483, and #615706); also known as ''question-mark ear syndrome'' or ''dysgnathia complex'', is a rare craniofacial malformation of first and second branchial arches with a prevalence of <1/1,000,000. It is characterized by a distinctive auricular malformation (question mark ear (QME)) and highly variable mandibular anomalies. Variants found in PLCB4, GNAI3, and in EDN1 genes are responsible for >90% of tested ARCND patients. Whole exome sequencing in a multigenerational Egyptian kindred with high intrafamilial variability revealed a known heterozygous missense variant in PLCB4 (NM_000933.3:c.1862G>A:p.(Arg621His)). This report increases the number of molecularly characterized ARCND patients to 29 and emphasizes the highly variable clinical presentation within families.

Ear Diseases/genetics , Ear/abnormalities , Mutation , Phenotype , Phospholipase C beta/genetics , Adolescent , Adult , Child , Ear/pathology , Ear Diseases/pathology , Endothelin-1/genetics , Female , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Humans , Male , Pedigree
Eur J Hum Genet ; 28(8): 1044-1055, 2020 08.
Article En | MEDLINE | ID: mdl-32071410

Primrose syndrome is characterized by variable intellectual deficiency, behavior disorders, facial features with macrocephaly, and a progressive phenotype with hearing loss and ectopic calcifications, distal muscle wasting, and contractures. In 2014, ZBTB20 variants were identified as responsible for this syndrome. Indeed, ZBTB20 plays an important role in cognition, memory, learning processes, and has a transcription repressive effect on numerous genes. A more severe phenotype was discussed in patients with missense single nucleotide variants than in those with large deletions. Here, we report on the clinical and molecular results of 14 patients: 6 carrying ZBTB20 missense SNVs, 1 carrying an early truncating indel, and 7 carrying 3q13.31 deletions, recruited through the AnDDI-Rares network. We compared their phenotypes and reviewed the data of the literature, in order to establish more powerful phenotype-genotype correlations. All 57 patients presented mild-to-severe ID and/or a psychomotor delay. Facial features were similar with macrocephaly, prominent forehead, downslanting palpebral fissures, ptosis, and large ears. Hearing loss was far more frequent in patients with missense SNVs (p = 0.002), ectopic calcification, progressive muscular wasting, and contractures were observed only in patients with missense SNVs (p nonsignificant). Corpus callosum dysgenesis (p = 0.00004), hypothyroidism (p = 0.047), and diabetes were also more frequent in this group. However, the median age was 9.4 years in patients with deletions and truncating variant compared with 15.1 years in those with missense SNVs. Longer follow-up will be necessary to determine whether the phenotype of patients with deletions is also progressive.

Abnormalities, Multiple/genetics , Calcinosis/genetics , Ear Diseases/genetics , Intellectual Disability/genetics , Muscular Atrophy/genetics , Nerve Tissue Proteins/genetics , Phenotype , Transcription Factors/genetics , Abnormalities, Multiple/pathology , Adolescent , Calcinosis/pathology , Child , Child, Preschool , Chromosome Deletion , Chromosomes, Human, Pair 3/genetics , Corpus Callosum/diagnostic imaging , Ear Diseases/pathology , Humans , Intellectual Disability/pathology , Muscular Atrophy/pathology , Mutation, Missense
Paediatr Respir Rev ; 33: 24-27, 2020 Feb.
Article En | MEDLINE | ID: mdl-31734186

A laryngotracheoesophageal cleft (LC) is a rare congenital anomaly of the upper aerodigestive tract resulting from the absence of fusion of the posterior cricoid lamina, which affects an abnormal communication between the larynx, trachea and esophagus. The genetic etiology of LC remains elusive. The involvement of genetic factors in the development of LC is suggested by reports of familial occurrence, and the increased prevalence of component features among first-degree relatives of affected individuals and murine knockout models. No consistent pattern of inheritance has been found in nonsyndromic patients, except for cases associated with described syndromes. Once the syndrome related to the laryngeal cleft is considered, an active search for the cleft must be initiated. The genetic evaluation of patients with LCs should be guided by the type and location of the malformation, specific medical history and a detailed physical examination. The application of genetic approaches, such as microarrays and exome sequencing might lead to elucidating the etiology of LCs.

Anal Canal/abnormalities , Arthrogryposis/genetics , CHARGE Syndrome/genetics , Congenital Abnormalities/genetics , Craniofacial Abnormalities/genetics , DiGeorge Syndrome/genetics , Ear Diseases/genetics , Ear/abnormalities , Esophagus/abnormalities , Heart Defects, Congenital/genetics , Hypertelorism/genetics , Hypopituitarism/genetics , Hypospadias/genetics , Intellectual Disability/genetics , Kidney/abnormalities , Larynx/abnormalities , Limb Deformities, Congenital/genetics , Pallister-Hall Syndrome/genetics , Spine/abnormalities , Trachea/abnormalities , Congenital Abnormalities/diagnosis , Humans
Am J Med Genet A ; 182(3): 521-526, 2020 03.
Article En | MEDLINE | ID: mdl-31821719

Primrose syndrome is a congenital malformation syndrome characterized by intellectual disability, developmental delay, progressive muscle wasting, and ear lobe calcification. Mutations in the ZBTB20 gene have been established as being accountable for this syndrome. In this study, a novel de novo ZBTB20 mutation, NM_001164342.2:c.1945C>T (p.Leu649Phe), has been identified through whole exome sequencing (WES) in a female patient presenting a typical Primrose phenotype. Because the present patient exhibited recurrent otitis media, detailed immunological examinations were performed in this study and subnormal immunoglobulin levels were firstly identified in a Primrose patient. Anatomical anomaly of the inner ear has never been reported in this patient and WES data did not include any relevant variants causally linked with the immunologic defect. Thus, there is a possibility of a relation between an unclassified immunodeficiency with selective IgG2 deficiency and Primrose syndrome and this may be the reason of recurrent otitis media frequently observed in Primrose patients. Because subnormal levels of IgG2 in this patient might be caused by an unrelated and still uncharacterized genetic cause, further studies are required to prove the causal link between aberrant ZBTB20 function and immunodeficiency.

Abnormalities, Multiple/genetics , Calcinosis/genetics , Developmental Disabilities/genetics , Ear Diseases/genetics , Genetic Predisposition to Disease , Intellectual Disability/genetics , Muscular Atrophy/genetics , Nerve Tissue Proteins/genetics , Transcription Factors/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/pathology , Calcinosis/diagnosis , Calcinosis/pathology , Child , Developmental Disabilities/diagnosis , Developmental Disabilities/pathology , Ear Diseases/diagnosis , Ear Diseases/pathology , Female , Humans , Immunoglobulin G/genetics , Intellectual Disability/diagnosis , Intellectual Disability/pathology , Male , Muscular Atrophy/diagnosis , Muscular Atrophy/pathology , Mutation, Missense/genetics , Phenotype , Whole Exome Sequencing
Am J Med Genet A ; 179(11): 2228-2232, 2019 11.
Article En | MEDLINE | ID: mdl-31321892

Primrose syndrome (PRIMS), a rare genetic disorder with several clinical findings including intellectual disability, macrocephaly, typical facial features, and muscle wasting, is caused by heterozygous variants in the ZBTB20 gene. We report the cases of two males diagnosed with PRIMS at different ages, emphasizing the likely progressive nature of the disorder, as well as the differences and similarities of presentation during infancy and adulthood. Patient 1 is a 2-year-old American male with a medical history marked by impaired hearing, developmental delays, and fainting spells. Patient 2 is a 28-year-old Brazilian male, who presents with a phenotype similar to that seen in Patient 1 with additional features of ectopic calcifications and prominent muscular and skeletal abnormalities. Additionally, Patient 2 has a history of fainting spells and diminished body height and weight, with the latter features having only been reported in one PRIMS patient so far. Both Patients 1 and 2 were found to carry heterozygous likely pathogenic missense variants, detected in the last coding exon of ZBTB20 (c.1822T>C, p.Cys608Arg, de novo, and c.1873A>G, p.Met625Val, respectively), consistent with PRIMS. Overall, these case reports highlight PRIMS's likely progressive nature and contribute to the understanding of the natural history of this condition.

Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Calcinosis/diagnosis , Calcinosis/genetics , Ear Diseases/diagnosis , Ear Diseases/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Muscular Atrophy/diagnosis , Muscular Atrophy/genetics , Mutation , Nerve Tissue Proteins/genetics , Phenotype , Transcription Factors/genetics , Humans , Infant , Male
Am J Med Genet A ; 179(3): 344-349, 2019 03.
Article En | MEDLINE | ID: mdl-30637921

Primrose syndrome is a rare autosomal dominant condition caused by heterozygous missense variants within ZBTB20. Through an exome sequencing approach (as part of the Deciphering Developmental Disorders [DDD] study) we have identified five unrelated individuals with previously unreported, de novo ZBTB20 pathogenic missense variants. All five missense variants targeted the C2H2 zinc finger domains. This genotype-up approach has allowed further refinement of the Primrose syndrome phenotype. Major characteristics (>90% individuals) include an intellectual disability (most frequently in the moderate range), a recognizable facial appearance and brain MRI abnormalities, particularly abnormalities of the corpus callosum. Other frequent clinical associations (in 50-90% individuals) include sensorineural hearing loss (83%), hypotonia (78%), cryptorchidism in males (75%), macrocephaly (72%), behavioral issues (56%), and dysplastic/hypoplastic nails (57%). Based upon these clinical data we discuss our current management of patients with Primrose syndrome.

Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Calcinosis/diagnosis , Calcinosis/genetics , Ear Diseases/diagnosis , Ear Diseases/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Genetic Variation , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Muscular Atrophy/diagnosis , Muscular Atrophy/genetics , Nerve Tissue Proteins/genetics , Phenotype , Transcription Factors/genetics , Child , Child, Preschool , Facies , Female , Genetic Loci , Genotype , Humans , Magnetic Resonance Imaging , Male , Mutation
Hum Mutat ; 39(7): 959-964, 2018 07.
Article En | MEDLINE | ID: mdl-29737001

Primrose syndrome (PS) is a rare disorder characterized by macrocephaly, tall stature, intellectual disability, autistic traits, and disturbances of glucose metabolism with insulin-resistant diabetes and distal muscle wasting occurring in adulthood. The disorder is caused by functional dysregulation of ZBTB20, a transcriptional repressor controlling energetic metabolism and developmental programs. ZBTB20 maps in a genomic region that is deleted in the 3q13.31 microdeletion syndrome, which explains the clinical overlap between the two disorders. A narrow spectrum of amino acid substitutions in a restricted region of ZBTB20 encompassing the first and second zinc-finger motifs have been reported thus far. Here, we characterize clinically and functionally the first truncating mutation [(c.1024delC; p.(Gln342Serfs*42)] and a missense change affecting the third zinc-finger motif of the protein [(c.1931C > T; p.(Thr644Ile)]. Our data document that both mutations have dominant negative impact on wild-type ZBTB20, providing further evidence of the specific behavior of PS-causing mutations on ZBTB20 function.

Abnormalities, Multiple/genetics , Calcinosis/genetics , Ear Diseases/genetics , Genetic Predisposition to Disease , Intellectual Disability/genetics , Muscular Atrophy/genetics , Nerve Tissue Proteins/genetics , Transcription Factors/genetics , Abnormalities, Multiple/physiopathology , Calcinosis/physiopathology , Child , Child, Preschool , Chromosome Deletion , Chromosomes, Human, Pair 3/genetics , Comparative Genomic Hybridization , Ear Diseases/physiopathology , Female , Humans , Intellectual Disability/physiopathology , Male , Muscular Atrophy/physiopathology , Mutation, Missense/genetics , Zinc Fingers/genetics
Am J Med Genet A ; 176(5): 1091-1098, 2018 05.
Article En | MEDLINE | ID: mdl-29681083

Corpus callosum (CC) is the major brain commissure connecting homologous areas of cerebral hemispheres. CC anomalies (CCAs) are the most frequent brain anomalies leading to variable neurodevelopmental outcomes making genetic counseling difficult in the absence of a known etiology that might inform the prognosis. Here, we used whole exome sequencing, and a targeted capture panel of syndromic CCA known causal and candidate genes to screen a cohort of 64 fetuses with CCA observed upon autopsy, and 34 children with CCA and intellectual disability. In one fetus and two patients, we identified three novel de novo mutations in ZBTB20, which was previously shown to be causal in Primrose syndrome. In addition to CCA, all cases presented with additional features of Primrose syndrome including facial dysmorphism and macrocephaly or megalencephaly. All three variations occurred within two out of the five zinc finger domains of the transcriptional repressor ZBTB20. Through homology modeling, these variants are predicted to result in local destabilization of each zinc finger domain suggesting subsequent abnormal repression of ZBTB20 target genes. Neurohistopathological analysis of the fetal case showed abnormal regionalization of the hippocampal formation as well as a reduced density of cortical upper layers where originate most callosal projections. Here, we report novel de novo ZBTB20 mutations in three independent cases with characteristic features of Primrose syndrome including constant CCA. Neurohistopathological findings in fetal case corroborate the observed key role of ZBTB20 during hippocampal and neocortical development. Finally, this study highlights the crucial role of ZBTB20 in CC development in human.

Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Agenesis of Corpus Callosum/diagnosis , Agenesis of Corpus Callosum/genetics , Calcinosis/diagnosis , Calcinosis/genetics , Ear Diseases/diagnosis , Ear Diseases/genetics , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Muscular Atrophy/diagnosis , Muscular Atrophy/genetics , Mutation , Nerve Tissue Proteins/genetics , Transcription Factors/genetics , Adolescent , Amino Acid Sequence , Brain/abnormalities , Brain/diagnostic imaging , Child , Female , High-Throughput Nucleotide Sequencing , Humans , Infant, Newborn , Male , Nerve Tissue Proteins/chemistry , Nucleic Acid Conformation , Pedigree , Phenotype , Protein Conformation , Reproducibility of Results , Sequence Analysis, DNA , Transcription Factors/chemistry
Clin Genet ; 93(2): 356-359, 2018 02.
Article En | MEDLINE | ID: mdl-28456137

Auriculocondylar syndrome and isolated question mark ear result from dysregulation of the endothelin 1-endothelin receptor type A signaling pathway. Animal models have highlighted the role of the transcription factor MEF2C as an effector of this pathway. We report heterozygous MEF2C loss-of-function as a possible cause of question mark ear associated with intellectual deficiency.

Brain Diseases/genetics , Ear Diseases/genetics , Ear/abnormalities , Genetic Predisposition to Disease , Brain Diseases/physiopathology , Child, Preschool , Ear/physiopathology , Ear Diseases/physiopathology , Genetic Association Studies , Humans , Infant , Loss of Function Mutation/genetics , MEF2 Transcription Factors/genetics , Male , Pedigree , Phenotype
Am J Med Genet A ; 173(4): 938-945, 2017 Apr.
Article En | MEDLINE | ID: mdl-28328130

Auriculocondylar syndrome, mainly characterized by micrognathia, small mandibular condyle, and question mark ears, is a rare disease segregating in an autosomal dominant pattern in the majority of the families reported in the literature. So far, pathogenic variants in PLCB4, GNAI3, and EDN1 have been associated with this syndrome. It is caused by a developmental abnormality of the first and second pharyngeal arches and it is associated with great inter- and intra-familial clinical variability, with some patients not presenting the typical phenotype of the syndrome. Moreover, only a few patients of each molecular subtype of Auriculocondylar syndrome have been reported and sequenced. Therefore, the spectrum of clinical and genetic variability is still not defined. In order to address these questions, we searched for alterations in PLCB4, GNAI3, and EDN1 in patients with typical Auriculocondylar syndrome (n = 3), Pierre Robin sequence-plus (n = 3), micrognathia with additional craniofacial malformations (n = 4), or non-specific auricular dysplasia (n = 1), which could represent subtypes of Auriculocondylar syndrome. We found novel pathogenic variants in PLCB4 only in two of three index patients with typical Auriculocondylar syndrome. We also performed a detailed comparative analysis of the patients presented in this study with those previously published, which showed that the pattern of auricular abnormality and full cheeks were associated with molecularly characterized individuals with Auriculocondylar syndrome. Finally, our data contribute to a better definition of a set of parameters for clinical classification that may be used as a guidance for geneticists ordering molecular testing for Auriculocondylar syndrome. © 2017 Wiley Periodicals, Inc.

Ear Diseases/diagnosis , Ear/abnormalities , Genetic Predisposition to Disease , Micrognathism/diagnosis , Mutation , Phospholipase C beta/genetics , Pierre Robin Syndrome/diagnosis , Adult , Child , Ear/pathology , Ear Diseases/classification , Ear Diseases/genetics , Ear Diseases/pathology , Endothelin-1/genetics , Female , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Gene Expression , Genes, Dominant , High-Throughput Nucleotide Sequencing , Humans , Male , Micrognathism/classification , Micrognathism/genetics , Micrognathism/pathology , Pedigree , Phenotype , Pierre Robin Syndrome/classification , Pierre Robin Syndrome/genetics , Pierre Robin Syndrome/pathology , Terminology as Topic
Int J Pediatr Otorhinolaryngol ; 90: 64-69, 2016 Nov.
Article En | MEDLINE | ID: mdl-27729156

OBJECTIVE: The aim of this study was to analyse the genetic and non genetic risk factors for cisplatin ototoxicity. METHODS: This study was conducted on 72 children who received cisplatin based chemotherapy. Brock and Muenster classifications were used to evaluate ototoxicity seen in these children. 6 single nucleotide polymorphisms (SNP); ERCC1 rs 11615, GSTP1 rs1138272, GSTP1 rs1695, LRP2 rs 2075252, TPMT rs 12201199, COMT rs 9332377, were evaluated as genetic factors by real time PCR. Non genetic factors such as cranial irradiation, cumulative doses of cisplatin, age, gender, administration of other ototoxic drugs were analysed as well. By using Chi-square test, risk factors were matched with the ototoxicity classifications. Significant risk factors were reevaluated using logistic regression modelling. RESULTS: According to univariate analyses, male gender, co-treatment with aminoglycosides and mutant genotype of GSTP1 rs1695 were significantly related with cisplatin ototoxicity. Logistic regression modelling analyses also showed that male gender, co-treatment with aminoglycosides were found to be significantly related with cisplatin ototoxicity. Mutant genotype of GSTP1 rs1695 was not found to be significant, but close to the level of statistical significance. CONCLUSION: Male gender, co-treatment with aminoglycosides are significant risk factors for cisplatin ototoxicity in pediatric patients. Mutant genotype of GSTP1 rs1695 seems to be a genetic risk factor in univariate analyses, although not confirmed by multivariate analyses. Therefore, GSTP1 rs1695 SNP needs to be studied in larger series.

Aminoglycosides/adverse effects , Antineoplastic Agents/adverse effects , Cisplatin/adverse effects , Ear Diseases/chemically induced , Ear Diseases/genetics , Glutathione S-Transferase pi/genetics , Adolescent , Age Factors , Antineoplastic Agents/administration & dosage , Child , Child, Preschool , Cisplatin/administration & dosage , Drug Therapy, Combination/adverse effects , Female , Genotype , Humans , Infant , Male , Neoplasms/therapy , Polymorphism, Single Nucleotide , Prospective Studies , Radiotherapy/adverse effects , Risk Factors , Sex Factors
Otol Neurotol ; 37(10): 1583-1588, 2016 12.
Article En | MEDLINE | ID: mdl-27631835

OBJECTIVE: To investigate the prevalence and relative risk of semicircular canal dehiscence (SCD) in pediatric patients with CDH23 pathogenic variants (Usher syndrome or non-syndromic deafness) compared with age-matched controls. STUDY DESIGN: Retrospective cohort study. SETTING: Multi-institutional study. PATIENTS: Pediatric patients (ages 0-5 years) were compared based on the presence of biallelic pathogenic variants in CDH23 with pediatric controls who underwent computed tomography (CT) temporal bone scan for alternative purposes. INTERVENTIONS: Retrospective review of diagnostic high resolution CT temporal bone scans and magnetic resonance imaging (MRI) for evaluation of SCD. MAIN OUTCOME MEASURES: Superior and posterior semicircular canals were evaluated by a neuroradiologist for presence of SCD or abnormal development. RESULTS: Forty-two CT scans were reviewed for SCD. Eighty-six percent of the CDH23 variant group had abnormalities in at least one canal compared with only 12% in age-matched controls. In the CDH23 variant group there were four patients with superior SCD (57%, RR = 10.0) and three patients with posterior canal abnormalities (43%, RR = 7.5) compared with two, and two patients, respectively, in the control population. Four CDH23 variant children had bilateral abnormalities. One child had thinning or dehiscence in both the superior and posterior canals. Relative risk of SCD in children with CDH23 pathogenic variants is 7.5 (p < 0.001) compared with the pediatric control population. CONCLUSIONS: Children with a CDH23 pathogenic variants are at significantly increased risk of having SCD and this may be a contributing factor to the vestibular dysfunction in Usher syndrome type 1D patient population.

Cadherins/genetics , Ear Diseases/genetics , Semicircular Canals/pathology , Alleles , Child, Preschool , Ear Diseases/diagnostic imaging , Ear Diseases/epidemiology , Ear Diseases/pathology , Female , Genetic Predisposition to Disease , Genotype , Humans , Infant , Infant, Newborn , Magnetic Resonance Imaging , Male , Prevalence , Retrospective Studies , Risk Factors , Semicircular Canals/diagnostic imaging , Tomography, X-Ray Computed
Sci Signal ; 9(423): eg6, 2016 Apr 12.
Article En | MEDLINE | ID: mdl-27072653

This Focus Issue highlights new discoveries at the level of the receptor, the α subunit, and the ßγ subunit and spans research in yeast on polarized growth and G protein-coupled receptor (GPCR) trafficking, in mice on an orphan GPCR with constitutive activity, and a disease-causing mutation in an α subunit that results in inappropriate GPCR-G protein coupling.

Ear Diseases/genetics , Ear/abnormalities , GTP-Binding Proteins/genetics , Mutation , Receptors, G-Protein-Coupled/genetics , Signal Transduction/genetics , Animals , Ear Diseases/metabolism , GTP-Binding Proteins/metabolism , Humans , Protein Subunits/genetics , Protein Subunits/metabolism , Receptors, G-Protein-Coupled/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/growth & development , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism