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Eur J Obstet Gynecol Reprod Biol ; 263: 176-180, 2021 Aug.
Article En | MEDLINE | ID: mdl-34218205

OBJECTIVE: To evaluate the prognosis of fetuses with a prenatal diagnosis of micrognathia in the first trimester. STUDY DESIGN: Over a 3-year period, patients with fetal micrognathia were detected at the time of nuchal translucency screening. The medical records of these pregnancies were reviewed, including maternal demographics, sonographic findings, genetic testing results and pregnancy outcomes. RESULTS: Forty-three cases of first-trimester micrognathia were included in this study. Chromosomal abnormalities were detected in seven cases. Of the fetuses with a normal array, further investigation of monogenic disorders with whole-exome sequencing was undertaken in 13 cases. Monogenic syndromes were identified in eight cases, including six with de-novo dominant alleles and two with recessive conditions. Whole-exome sequencing was refused in 23 cases; among these, other additional anomalies were found on anatomic ultrasound in 10 cases. CONCLUSION: This study demonstrated that caution should be adopted when finding an apparently isolated micrognathia in early gestation, even with a normal array. A diagnosis of genetic syndrome or multiple anomalies on subsequent scans is most likely, and will affect the final prognosis.

Micrognathism , Female , Fetus/diagnostic imaging , Humans , Micrognathism/diagnostic imaging , Micrognathism/genetics , Nuchal Translucency Measurement , Pregnancy , Pregnancy Trimester, First , Prenatal Diagnosis , Ultrasonography, Prenatal
Genes (Basel) ; 12(6)2021 06 19.
Article En | MEDLINE | ID: mdl-34205270

Coffin-Siris syndrome (CSS, MIM 135900) is a multi-system intellectual disability syndrome characterized by classic dysmorphic features, developmental delays, and organ system anomalies. Genes in the BRG1(BRM)-associated factors (BAF, Brahma associated factor) complex have been shown to be causative, including ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, and SOX4. In order to describe more robust genotype-phenotype correlations, we collected data from 208 individuals from the CSS/BAF complex registry with pathogenic variants in seven of these genes. Data were organized into cohorts by affected gene, comparing genotype groups across a number of binary and quantitative phenotypes. We determined that, while numerous phenotypes are seen in individuals with variants in the BAF complex, hypotonia, hypertrichosis, sparse scalp hair, and hypoplasia of the distal phalanx are still some of the most common features. It has been previously proposed that individuals with ARID-related variants are thought to have more learning and developmental struggles, and individuals with SMARC-related variants, while they also have developmental delay, tend to have more severe organ-related complications. SOX-related variants also have developmental differences and organ-related complications but are most associated with neurodevelopmental differences. While these generalizations still overall hold true, we have found that all individuals with BAF-related conditions are at risk of many aspects of the phenotype, and management and surveillance should be broad.

Abnormalities, Multiple/genetics , Face/abnormalities , Genotype , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Micrognathism/genetics , Neck/abnormalities , Phenotype , Abnormalities, Multiple/pathology , Face/pathology , Hand Deformities, Congenital/pathology , Humans , Intellectual Disability/pathology , Micrognathism/pathology , Mutation , Neck/pathology , Transcription Factors/genetics
J Pediatr Rehabil Med ; 14(3): 525-532, 2021.
Article En | MEDLINE | ID: mdl-34180430

BACKGROUND: Coffin-Siris syndrome is a rare genetic disease with heterozygous variants in the ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCE1 or SOX11 genes. It may manifest with somatic anomalies, deafness, urogenital malformations, recurrent infections, mental retardation, speech deficit, agenesis of the corpus callosum, convulsions, hypotonia, developmental delay, and scoliosis. CASE REPORT: A 14-year-old boy with Coffin-Siris syndrome due to variants in the ARID1A gene was referred to the clinic. His rehabilitation over a 9-year period was described. The problem of assessment and the approach to rehabilitation was discussed, enabling a progressive remodelling of the cognitive-behavioural disorders that most hindered the possibility of his acquiring new skills and achieving social and family integration. CLINICAL REHABILITATION: A protracted, customised, multiprofessional rehabilitation approach, centred on realistic functional objectives, implemented with the direct involvement of the family and school, was the only way to achieve the maximum independence and social and family integration permitted by his residual disability.

Hand Deformities, Congenital , Intellectual Disability , Micrognathism , Abnormalities, Multiple , Adolescent , Chromosomal Proteins, Non-Histone , Cognition , DNA Helicases , DNA-Binding Proteins , Face/abnormalities , Hand Deformities, Congenital/genetics , Humans , Intellectual Disability/genetics , Male , Micrognathism/genetics , Neck/abnormalities , Nuclear Proteins , Transcription Factors
Nat Commun ; 12(1): 833, 2021 02 05.
Article En | MEDLINE | ID: mdl-33547280

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment.

Developmental Disabilities/genetics , Gene Expression Regulation, Developmental , Microcephaly/genetics , Micrognathism/genetics , Peptide Initiation Factors/genetics , RNA-Binding Proteins/genetics , Adolescent , Amino Acid Sequence , Animals , Child , Developmental Disabilities/metabolism , Developmental Disabilities/pathology , Embryo, Nonmammalian , Female , Humans , Lysine/analogs & derivatives , Lysine/genetics , Lysine/metabolism , Male , Microcephaly/metabolism , Microcephaly/pathology , Micrognathism/metabolism , Micrognathism/pathology , Peptide Initiation Factors/deficiency , Peptides/genetics , Peptides/metabolism , Protein Biosynthesis , Protein Conformation , Protein Isoforms/deficiency , Protein Isoforms/genetics , Ribosomes/genetics , Ribosomes/metabolism , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/growth & development , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Sequence Alignment , Sequence Homology, Amino Acid , Spermidine/pharmacology , Zebrafish , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolism
Eur J Med Genet ; 64(4): 104182, 2021 Apr.
Article En | MEDLINE | ID: mdl-33639314

Disruption of the initiation of DNA replication is significantly associated with Meier-Gorlin syndrome (MGORS), an autosomal recessive condition of reduced growth, microtia and patellar a/hypoplasia. Biallelic mutations in CDC45, a member of the pre-initiation complex in DNA replication, cause a spectrum of phenotypes ranging from MGORS with craniosynostosis, through to isolated short stature and craniosynostosis. Here we report two affected sibs with MGORS and craniosynostosis, with biallelic variants in CDC45 identified by 10X Chromium whole genome sequencing. One variant is a frameshift mutation, predicted to be pathogenic, and is inherited in trans with a synonymous variant in a non-canonical exon (exon 7) of CDC45. An in vitro splicing assay showed that while the canonical CDC45 exon 6-exon 8 transcript (with skipping of exon 7; numbering as per NM001178010.2) remained as the predominant transcript, the variant allele induced the use of novel splice acceptor sites in intron 6, all of which produced transcripts harbouring premature stop codons. This perturbation of canonical splicing provides evidence that this synonymous variant is indeed a deleterious alteration in this family. This report adds to the initial patient cohort in which several synonymous variants were also described, further highlighting the contribution of this variant type in CDC45. It also reiterates the true potential pathogenicity of synonymous variants, which is a mutation type that is commonly ignored in variant prioritization strategies.

Cell Cycle Proteins/genetics , Congenital Microtia/genetics , Craniosynostoses/genetics , Growth Disorders/genetics , Micrognathism/genetics , Mutation , Patella/abnormalities , RNA Splice Sites , Cell Cycle Proteins/metabolism , Cells, Cultured , Child , Child, Preschool , Congenital Microtia/pathology , Craniosynostoses/pathology , Exons , Growth Disorders/pathology , Humans , Male , Micrognathism/pathology , Patella/pathology , Pedigree
Am J Med Genet A ; 185(4): 1317-1320, 2021 04.
Article En | MEDLINE | ID: mdl-33372358

A Sri Lankan male child with supraorbital hyperostosis, broad nasal bridge, small mandible, severe kyphoscoliosis, distal joint contractures of the hands and long second and third toes is described. A hemizygous pathogenic variant in exon 22 of the filamin A (FLNA) gene [NM_001110556.1: c.3557C>T; which leads to a nonsynonymous substitution of serine by leucine at codon 1186 in the FLNA protein; NP_001104026.1: p.Ser1186Leu] was identified. The clinical features observed in this patient were consistent with the cardinal manifestations seen in frontometaphyseal dysplasia 1 (FMD1). However, characteristic extra skeletal manifestations such as cardiac defects, uropathy, and hearing impairment which have previously been reported in association with this condition were absent in this patient.

Bone Diseases, Developmental/genetics , Filamins/genetics , Forehead/abnormalities , Genetic Predisposition to Disease , Osteochondrodysplasias/genetics , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Bone Diseases, Developmental/pathology , Child , Exons/genetics , Forehead/pathology , Humans , Male , Micrognathism/genetics , Micrognathism/pathology , Mutation, Missense/genetics , Osteochondrodysplasias/pathology , Phenotype , Sri Lanka/epidemiology
Am J Med Genet A ; 185(3): 871-876, 2021 03.
Article En | MEDLINE | ID: mdl-33338304

Meier-Gorlin syndrome is an autosomal recessively inherited disorder of growth retardation, accompanied by microtia and patellae a/hypoplasia and characteristic facies. Pathogenic variants in genes associated with the initiation of DNA replication underlie the condition, with biallelic variants in CDT1 the most common cause. Using 10× Chromium genome sequencing, we report CDT1 variants in an adult female, with an inframe amino acid deletion inherited in trans with a deep intronic variant which likely serves as the branchpoint site in Intron 8. Splicing defects arising from this variant were confirmed through in vitro analysis. At 49 years, she represents the oldest patient with a molecular diagnosis described in the literature and is the first reported patient with Meier-Gorlin syndrome to have carried a successful pregnancy to term. Both of her pregnancies were complicated by postpartum hemorrhage and upon subsequent necessary hysterectomy, revealed uterine abnormalities. There is scant knowledge on reproductive ability and success in patients with Meier-Gorlin syndrome. Successful pregnancies among other clinically recognizable forms of primordial dwarfism have also not been described previously. This case is therefore of clinical interest for many forms of inherited growth retardation, and will assist in providing more information and clinical guidance for females of reproductive age.

Cell Cycle Proteins/genetics , Congenital Microtia/genetics , Frameshift Mutation , Growth Disorders/genetics , Micrognathism/genetics , Patella/abnormalities , Point Mutation , Pregnancy Complications/genetics , Alleles , Alternative Splicing , Base Sequence , Cell Cycle Proteins/deficiency , Codon, Nonsense/genetics , Female , Haplotypes/genetics , Humans , Introns/genetics , Middle Aged , Parity , Phenotype , Postpartum Hemorrhage/genetics , Pregnancy , Sequence Deletion , Uterus/abnormalities , Uterus/pathology , Whole Genome Sequencing
Am J Med Genet A ; 185(3): 995-998, 2021 03.
Article En | MEDLINE | ID: mdl-33369179

Mandibular hypoplasia, deafness, progeroid feature, and lipodystrophy syndrome (MDPL, MIM# 615381) is an extremely rare and recently recognized early adult onset of progeroid syndrome, with features of generalized lipodystrophy, dysmorphic features, telangiectasia, early onset hearing loss, insulin resistance, and dyslipidemia. Here, we present a 31-year-old Chinese woman with MDPL, harboring the recurrent pathogenic variant p.(Ser605del) in POLD1, illustrating the evolving manifestations of this premature aging disorder from infancy to adulthood.

Abnormalities, Multiple/genetics , DNA Polymerase III/genetics , Lipodystrophy, Congenital Generalized/genetics , Micrognathism/genetics , Progeria/genetics , Adult , DNA Polymerase III/deficiency , Deafness/genetics , Disease Progression , Dyslipidemias/genetics , Female , Genes, Dominant , Humans , Insulin Resistance/genetics , Myopia/genetics , Syndrome , Telangiectasis/genetics , Thinness/genetics
Article En | MEDLINE | ID: mdl-33154040

The archain 1 (ARCN1) gene encodes the coatomer subunit delta protein and is a component of the COPI coatomer complex, which is involved in retrograde vesical trafficking from the Golgi complex to the endoplasmic reticulum. Variants in ARCN1 have recently been associated with rhizomelic short stature with microcephaly, microretrognathia, and developmental delay. Here we report a 3.5-yr-old boy with microcephaly, global developmental delay, and multiple congenital abnormalities and the ARCN1-related syndrome caused by a novel de novo intronic variant. Whole-exome sequencing of the proband and his parents was utilized to determine the genetic origin of the patient's disorder and identified a de novo variant, NM_001655.5:c.654-15A > G, in the ARCN1 gene. Follow-up functional characterization of mRNA from the patient demonstrated that this variant creates a splicing defect of the ARCN1 mRNA. ARCN1-related syndrome represents an emerging disorder of developmental delay, and this report represents the sixth described patient. Despite the few instances reported in literature, the phenotype is consistent between our patient and previously reported individuals.

Coatomer Protein/genetics , Developmental Disabilities/genetics , Micrognathism/genetics , Abnormalities, Multiple/genetics , Child, Preschool , Deglutition Disorders/genetics , Endoplasmic Reticulum , Genetic Predisposition to Disease , Golgi Apparatus , Humans , Hypospadias/genetics , Male , Microcephaly/genetics , Micrognathism/diagnostic imaging , Pectus Carinatum/genetics , Phenotype , RNA, Messenger , Whole Exome Sequencing
Genetics ; 216(4): 995-1007, 2020 12.
Article En | MEDLINE | ID: mdl-33037049

Meier-Gorlin syndrome (MGS) is a rare, autosomal recessive disorder characterized by microtia, primordial dwarfism, small ears, and skeletal abnormalities. Patients with MGS often carry mutations in genes encoding the subunits of the Origin Recognition Complex (ORC), components of the prereplicative complex and replication machinery. Orc6 is an important component of ORC and has functions in both DNA replication and cytokinesis. A mutation in the conserved C-terminal motif of Orc6 associated with MGS impedes the interaction of Orc6 with core ORC. Recently, a new mutation in Orc6 was also identified; however, it is localized in the N-terminal domain of the protein. To study the functions of Orc6, we used the human gene to rescue the orc6 deletion in Drosophila Using this "humanized" Orc6-based Drosophila model of MGS, we discovered that unlike the previous Y225S MGS mutation in Orc6, the K23E substitution in the N-terminal TFIIB-like domain of Orc6 disrupts the protein ability to bind DNA. Our studies revealed the importance of evolutionarily conserved and variable domains of Orc6 protein, and allowed the studies of human protein functions and the analysis of the critical amino acids in live animal heterologous system, as well as provided novel insights into the mechanisms underlying MGS pathology.

Congenital Microtia/genetics , Growth Disorders/genetics , Micrognathism/genetics , Origin Recognition Complex/genetics , Patella/abnormalities , Animals , Binding Sites , Conserved Sequence , Drosophila melanogaster , Humans , Mutation , Origin Recognition Complex/chemistry , Origin Recognition Complex/metabolism , Protein Binding , Transgenes
Am J Med Genet C Semin Med Genet ; 184(3): 644-655, 2020 09.
Article En | MEDLINE | ID: mdl-32888375

Mosaic genetic mutations may be somatic, germline, or "gonosomal" and have the potential to cause genetic syndromes, disorders, or malformations. Mutations can occur at any point in embryonic development and the timing determines the extent of distribution of the mutation throughout the body and different tissue types. The eye and visual pathway offer a unique opportunity to study somatic and gonosomal mosaic mutations as the eye consists of tissues derived from all three germ layers allowing disease pathology to be assessed with noninvasive imaging. In this review, we describe systemic and ocular manifestations in a child with mosaic Coffin-Siris syndrome. The patient presented with a significant medical history of accommodative esotropia and hyperopia, macrocephaly, polydactyly, global developmental delay, hypotonia, ureteropelvic junction (UPJ) obstruction, and brain MRI abnormalities. The ophthalmic findings in this patient were nonspecific, however, they are consistent with ocular manifestations reported in other patients with Coffin-Siris syndrome. We also review ophthalmic findings of select mosaic chromosomal and single-gene disorders. Ophthalmic assessment alongside clinical genetic testing may play an important role in diagnosis of genetic syndromes as well as understanding disease pathology, particularly when mosaicism plays a role.

Abnormalities, Multiple/genetics , Brain/diagnostic imaging , DNA-Binding Proteins/genetics , Face/abnormalities , Genetic Predisposition to Disease , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Micrognathism/genetics , Neck/abnormalities , Transcription Factors/genetics , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/pathology , Brain/abnormalities , Child , Child, Preschool , Face/diagnostic imaging , Face/pathology , Female , Hand Deformities, Congenital/diagnostic imaging , Hand Deformities, Congenital/pathology , Humans , Infant , Intellectual Disability/diagnostic imaging , Intellectual Disability/pathology , Male , Micrognathism/diagnostic imaging , Micrognathism/pathology , Mosaicism , Mutation/genetics , Neck/diagnostic imaging , Neck/pathology , Nuclear Proteins/genetics , Phenotype
Taiwan J Obstet Gynecol ; 59(5): 763-765, 2020 Sep.
Article En | MEDLINE | ID: mdl-32917333

OBJECTIVE: We present prenatal diagnosis of a de novo 1.651-Mb 19q13.42-q13.43 microdeletion in a fetus with micrognathia and bilateral pyelectasis on prenatal ultrasound. CASE REPORT: A 32-year-old woman underwent amniocentesis at 28 weeks of gestation because of fetal micrognathia and bilateral pyelectasis on prenatal ultrasound. Amniocentesis revealed a karyotype of 46,XX. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed the result of arr 19q13.42q13.43 (55,028,722-56,680,564) × 1.0 [GRCh37 (hg19)] or a 1.651-Mb microdeletion encompassing 44 Online Mendelian Inheritance in Man (OMIM) genes including NLRP7, GP6, TNNT1, TNNI3 and DNAAF3. The parents did not have such a deletion and decided to continue the pregnancy. At 37 weeks of gestation, a 2560-g female baby was delivered by cesarean section because of oligohydramnios and decreased fetal movements. The baby manifested cleft palate, micrognathia and retrognathia at birth. She was doing well at age three months. Her body weight was 5.3 Kg (15th-25th centile), and body length was 59.2 cm (25th-50th centile). Renal sonogram showed bilateral mild pelvic dilation. She manifested no psychomotor retardation and no other internal organ abnormalities during pediatric follow-ups. CONCLUSION: A 19q13.42-q13.43 microdeletion can be associated with micrognathia, retrognathia, cleft palate and bilateral pyelectasis at birth.

Chromosome Deletion , Chromosomes, Human, Pair 19/genetics , Cleft Palate/genetics , Micrognathism/genetics , Pyelectasis/genetics , Adult , Amniocentesis/methods , Cesarean Section , Cleft Palate/diagnosis , Comparative Genomic Hybridization , Female , Humans , Infant, Newborn , Micrognathism/diagnostic imaging , Pregnancy , Pyelectasis/diagnostic imaging , Ultrasonography, Prenatal
Am J Med Genet A ; 182(10): 2253-2262, 2020 10.
Article En | MEDLINE | ID: mdl-32851773

Coffin-Siris syndrome (CSS; OMIM #135900) is a rare, multisystem syndrome caused by pathogenic variants in genes encoding the BRG-1 associated factors complex (BAF). Individuals with CSS often present with feeding difficulties and failure to thrive during infancy, in addition to a number of variable congenital anomalies. Nutritional interventions are used to support growth in this population, and growth hormone therapy has been reported in a limited number of cases. The purpose of this study was to construct CSS-specific growth charts to better characterize the growth in this population. Anthropometric data were collected from 99 individuals enrolled in the CSS/BAF pathway international registry via a retrospective chart review. All measurements obtained after the first exposure to growth hormone therapy were excluded from this analysis. Sex-specific centiles (5th, 50th, and 95th) were estimated for height, weight, and head circumference from birth to age 10. Cubic smoothing splines were then fit to the centile estimates and superimposed on normative male and female growth curves for comparison. The CSS patients in this cohort exhibited normal growth parameters at birth. By age 10, the weight and head circumference of the CSS cohort began to approach normal parameters. Stature, however, remained shortened at 10 years of age.

Abnormalities, Multiple/genetics , DNA Helicases/genetics , Face/abnormalities , Genetic Association Studies , Genetic Predisposition to Disease , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Micrognathism/genetics , Neck/abnormalities , Nuclear Proteins/genetics , Transcription Factors/genetics , Child , Child, Preschool , Face/physiology , Female , Growth Charts , Humans , Infant , Infant, Newborn , Male , Neck/physiology
Am J Med Genet A ; 182(9): 2058-2067, 2020 09.
Article En | MEDLINE | ID: mdl-32686290

SMARCA4 encodes a central ATPase subunit in the BRG1-/BRM-associated factors (BAF) or polybromo-associated BAF (PBAF) complex in humans, which is responsible in part for chromatin remodeling and transcriptional regulation. Variants in this and other genes encoding BAF/PBAF complexes have been implicated in Coffin-Siris Syndrome, a multiple congenital anomaly syndrome classically characterized by learning and developmental differences, coarse facial features, hypertrichosis, and underdevelopment of the fifth digits/nails of the hands and feet. Individuals with SMARCA4 variants have been previously reported and appear to display a variable phenotype. We describe here a cohort of 15 unrelated individuals with SMARCA4 variants from the Coffin-Siris syndrome/BAF pathway disorders registry who further display variability in severity and degrees of learning impairment and health issues. Within this cohort, we also report two individuals with novel nonsense variants who appear to have a phenotype of milder learning/behavioral differences and no organ-system involvement.

Abnormalities, Multiple/genetics , DNA Helicases/genetics , DNA-Binding Proteins/genetics , Face/abnormalities , Genetic Predisposition to Disease , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Micrognathism/genetics , Neck/abnormalities , Nuclear Proteins/genetics , Transcription Factors/genetics , Abnormalities, Multiple/epidemiology , Abnormalities, Multiple/pathology , Adolescent , Child , Child, Preschool , Chromosomal Proteins, Non-Histone/genetics , Codon, Nonsense/genetics , Face/pathology , Female , Genetic Association Studies , Hand Deformities, Congenital/epidemiology , Hand Deformities, Congenital/pathology , Humans , Infant , Intellectual Disability/epidemiology , Intellectual Disability/pathology , Male , Micrognathism/epidemiology , Micrognathism/pathology , Neck/pathology , Phenotype
Eur J Med Genet ; 63(10): 104005, 2020 Oct.
Article En | MEDLINE | ID: mdl-32693209

9p duplication syndrome is a common congenital anomaly syndrome with specific facial features, mental and developmental retardations, and characteristic fingers. Pure 9p duplication without other chromosomal structural variations is very rare. It has recently been reported that cases with partial 9p duplication including SMARCA2 have phenotypes overlapping with Coffin-Siris syndrome (CSS). Herein, we present a family with pure 9p duplication syndrome in which phenotypes partially characteristic of CSS were identified. In one of two siblings, X-ray examination revealed hypoplasia of the distal phalanges of the fifth fingers, aplasia of the middle phalanges of the fifth fingers, and aplasia of the distal phalanges of the second to fifth toes. In pure 9p duplication together with our one affected case, 9 out of 14 cases (64.3%), excluding cases whose clinical data were unavailable, presented the absence or hypoplasia of the middle phalanges of fingers or toes. Interestingly, there are no reports on CSS with aplasia or hypoplasia of the middle phalanx. Therefore, this family might suggest that the aplasia or hypoplasia of the middle phalanges of the fifth fingers or toes is a distinct finding that can distinguish between pure 9p duplication and CSS.

Abnormalities, Multiple/genetics , Face/abnormalities , Finger Phalanges/abnormalities , Fingers/abnormalities , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Micrognathism/genetics , Neck/abnormalities , Toes/abnormalities , Transcription Factors/genetics , Trisomy/genetics , Abnormalities, Multiple/diagnostic imaging , Chromosomes, Human, Pair 9/genetics , Face/diagnostic imaging , Female , Hand Deformities, Congenital/diagnostic imaging , Humans , Infant, Newborn , Intellectual Disability/diagnostic imaging , Magnetic Resonance Imaging , Male , Micrognathism/diagnostic imaging , Neck/diagnostic imaging , Phenotype , Pregnancy , Siblings
Clin Genet ; 98(2): 147-154, 2020 08.
Article En | MEDLINE | ID: mdl-32385905

Variants in the FIG4 gene, which encodes a phosphatidylinositol-3,5-bisphosphatase lead to obstruction of endocytic trafficking, causing accumulation of enlarged vesicles in murine peripheral neurons and fibroblasts. Bi-allelic pathogenic variants in FIG4 are associated with neurological disorders including Charcot-Marie-Tooth disease type-4J (CMT4J) and Yunis-Varón syndrome (YVS). We present four probands from three unrelated families, all homozygous for a recurrent FIG4 missense variant c.506A>C p.(Tyr169Ser), with a novel phenotype involving features of both CMT4J and YVS. Three presented with infant-onset dystonia and one with hypotonia. All have depressed lower limb reflexes and distal muscle weakness, two have nerve conduction studies (NCS) consistent with severe sensorimotor demyelinating peripheral neuropathy and one had NCS showing patchy intermediate/mildly reduced motor conduction velocities. All have cognitive impairment and three have swallowing difficulties. MRI showed cerebellar atrophy and bilateral T2 hyperintense medullary swellings in all patients. These children represent a novel clinicoradiological phenotype and suggest that phenotypes associated with FIG4 missense variants do not neatly fall into previously described diagnoses but can present with variable features. Analysis of this gene should be considered in patients with central and peripheral neurological signs and medullary radiological changes, providing earlier diagnosis and informing reproductive choices.

Charcot-Marie-Tooth Disease/genetics , Cleidocranial Dysplasia/genetics , Ectodermal Dysplasia/genetics , Flavoproteins/genetics , Genetic Predisposition to Disease , Limb Deformities, Congenital/genetics , Micrognathism/genetics , Phosphoric Monoester Hydrolases/genetics , Age of Onset , Charcot-Marie-Tooth Disease/complications , Charcot-Marie-Tooth Disease/pathology , Child , Child, Preschool , Cleidocranial Dysplasia/complications , Cleidocranial Dysplasia/pathology , Dystonia/complications , Dystonia/genetics , Dystonia/pathology , Ectodermal Dysplasia/complications , Ectodermal Dysplasia/pathology , Female , Genotype , Humans , Limb Deformities, Congenital/complications , Limb Deformities, Congenital/pathology , Male , Micrognathism/complications , Micrognathism/pathology , Muscle Hypotonia/complications , Muscle Hypotonia/genetics , Muscle Hypotonia/pathology , Mutation/genetics , Pedigree , Phenotype
Dev Dyn ; 249(8): 924-945, 2020 08.
Article En | MEDLINE | ID: mdl-32315467

Mutations in core components of the spliceosome are responsible for a group of syndromes collectively known as spliceosomopathies. Patients exhibit microcephaly, micrognathia, malar hypoplasia, external ear anomalies, eye anomalies, psychomotor delay, intellectual disability, limb, and heart defects. Craniofacial malformations in these patients are predominantly found in neural crest cells-derived structures of the face and head. Mutations in eight genes SNRPB, RNU4ATAC, SF3B4, PUF60, EFTUD2, TXNL4, EIF4A3, and CWC27 are associated with craniofacial spliceosomopathies. In this review, we provide a brief description of the normal development of the head and the face and an overview of mutations identified in genes associated with craniofacial spliceosomopathies. We also describe a model to explain how and when these mutations are most likely to impact neural crest cells. We speculate that mutations in a subset of core splicing factors lead to disrupted splicing in neural crest cells because these cells have increased sensitivity to inefficient splicing. Hence, disruption in splicing likely activates a cellular stress response that includes increased skipping of regulatory exons in genes such as MDM2 and MDM4, key regulators of P53. This would result in P53-associated death of neural crest cells and consequently craniofacial malformations associated with spliceosomopathies.

Craniofacial Abnormalities/genetics , Intellectual Disability/genetics , Psychomotor Disorders/genetics , Spliceosomes/physiology , Animals , Cell Cycle Proteins/genetics , Choanal Atresia/genetics , Cyclophilins/genetics , DEAD-box RNA Helicases/genetics , Deafness/congenital , Deafness/genetics , Disease Models, Animal , Eukaryotic Initiation Factor-4A/genetics , Exons , Facies , Heart Defects, Congenital/genetics , Humans , Mice , Microcephaly/genetics , Micrognathism/genetics , Mutation , Neural Crest/cytology , Neural Crest/metabolism , Neuroepithelial Cells/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-mdm2/genetics , RNA Splicing Factors/genetics , Ribonucleoprotein, U5 Small Nuclear/genetics , Syndrome , Tumor Suppressor Protein p53/genetics
Parkinsonism Relat Disord ; 74: 6-11, 2020 05.
Article En | MEDLINE | ID: mdl-32268254

BACKGROUND: Charcot-Marie-Tooth disease type 4J (CMT4J) originates from mutations in the FIG4 gene and leads to distal muscle weakness. Two null alleles of FIG4 cause Yunis Varón syndrome with severe central nervous system involvement, cleidocranial dysmorphism, absent thumbs and halluces and early death. OBJECTIVES: To analyse the phenotypic spectrum of FIG4-related disease and explore effects of residual FIG4 protein. METHODS: Phenotyping of five new patients with FIG4-related disease. Western Blot analyses of FIG4 from patient fibroblasts. RESULTS: Next generation sequencing revealed compound heterozygous variants in FIG4 in five patients. All five patients presented with peripheral neuropathy, various degree of dysmorphism and a central nervous system involvement comprising Parkinsonism in 3/5 patients, cerebellar ataxia (1/5), spasticity of lower limbs (1/5), epilepsy (1/5) and/or cognitive deficits (2/5). Onset varied between the first and the seventh decade. There was no residual FIG4 protein detectable in fibroblasts of the four analysed patients. CONCLUSION: This study extends the phenotypic spectrum of FIG4-related disease to Parkinsonism as a feature and demonstrates new phenotypes on a continuum between CMT4J and Yunis Varón syndrome.

Charcot-Marie-Tooth Disease/genetics , Cleidocranial Dysplasia/genetics , Ectodermal Dysplasia/genetics , Flavoproteins/genetics , Limb Deformities, Congenital/genetics , Micrognathism/genetics , Parkinsonian Disorders/genetics , Phosphoric Monoester Hydrolases/genetics , Adult , Aged , Charcot-Marie-Tooth Disease/physiopathology , Cleidocranial Dysplasia/physiopathology , Ectodermal Dysplasia/physiopathology , Female , Fibroblasts , Humans , Limb Deformities, Congenital/physiopathology , Male , Micrognathism/physiopathology , Middle Aged , Mutation , Parkinsonian Disorders/physiopathology , Pedigree , Phenotype , Young Adult