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Bone ; 153: 116152, 2021 12.
Article En | MEDLINE | ID: mdl-34400385

Acrofrontofacionasal dysostosis type 1 (AFFND1) is an extremely rare disorder characterized by several dysmorphic features, skeletal abnormalities and intellectual disability, and described only in seven patients in the literature. A biallelic variant in the Neuroblastoma Amplified Sequence (NBAS) gene was recently identified in two Indian patients with AFFND1. Here we report genetic investigation of AFFND1 in the originally described Brazilian families and the identification of an extremely rare, recessively-inherited, intronic variant in the Phosphatidylinositol Glycan class B (PIGB) gene NC_000015.10 (NM_004855.4): c.795-19T > G) in the affected individuals. The PIGB gene encodes an enzyme involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, which is required for the post-translational modification of a large variety of proteins, enabling their correct cellular localization and function. Recessive variants in PIGB have previously been reported in individuals with a neurodevelopmental syndrome having partial overlap with AFFND1. In vitro assays demonstrated that the intronic variant leads to exon skipping, suggesting the Brazilian AFFND1 patients may be null for PIGB, in agreement with their severe clinical phenotype. These data increase the number of pathogenic variants in the PIGB gene, place AFFND1 among GPI deficiencies and extend the spectrum of phenotypes associated with GPI biosynthesis defects.

Glycosylphosphatidylinositols , Mandibulofacial Dysostosis , Humans , Mannosyltransferases/genetics , Mutation/genetics , Phenotype , Seizures
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
J Clin Invest ; 131(6)2021 03 15.
Article En | MEDLINE | ID: mdl-33497358

Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system, with an incidence of 1 in 5000 live births. Chronic intestinal pseudo-obstruction (CIPO) is less frequent and classified as neurogenic or myogenic. Isolated HSCR has an oligogenic inheritance with RET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes. Here, we describe a series of patients with developmental disorders including gastrointestinal dysmotility, and investigate the underlying molecular bases. Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis. Thorough gut histology revealed aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities. The cell type-specific ErbB3 and ErbB2 function was further analyzed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors. The consequences of the identified variants were evaluated using quantitative real-time PCR (RT-qPCR) on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing WT or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors. Our results demonstrate that dysregulation of ERBB3 or ERBB2 leads to a broad spectrum of developmental anomalies, including intestinal dysmotility.

Developmental Disabilities/genetics , Intestinal Pseudo-Obstruction/genetics , Mutation , Neuregulin-1/genetics , Receptor, ErbB-2/genetics , Receptor, ErbB-3/genetics , Adolescent , Animals , Child, Preschool , Developmental Disabilities/pathology , Disease Models, Animal , Female , Gastrointestinal Motility/genetics , Hirschsprung Disease/genetics , Hirschsprung Disease/pathology , Humans , Infant, Newborn , Intestinal Pseudo-Obstruction/pathology , Male , Mice , Models, Molecular , Pedigree , Phenotype , Pregnancy , Receptor, ErbB-2/chemistry , Receptor, ErbB-3/chemistry , Receptor, ErbB-3/deficiency
Hum Mol Genet ; 29(22): 3662-3678, 2020 12 04.
Article En | MEDLINE | ID: mdl-33276377

The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. LoF WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia.

Abnormalities, Multiple/genetics , DNA-Binding Proteins/genetics , Haploinsufficiency/genetics , Kidney/metabolism , RNA Splicing Factors/genetics , Abnormalities, Multiple/pathology , Anal Canal/abnormalities , Anal Canal/pathology , Animals , Esophagus/abnormalities , Esophagus/metabolism , Esophagus/pathology , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology , Heterozygote , Humans , Kidney/abnormalities , Kidney/pathology , Limb Deformities, Congenital/genetics , Limb Deformities, Congenital/pathology , Loss of Function Mutation/genetics , Mice , RNA Splicing/genetics , Spine/abnormalities , Spine/pathology , Trachea/abnormalities , Trachea/pathology
Am J Hum Genet ; 106(6): 779-792, 2020 06 04.
Article En | MEDLINE | ID: mdl-32413283

The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Here, we report bi-allelic loss-of-function variations in SMO in seven individuals from five independent families; these variations cause a wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. In addition, Hh-independent GLI2 accumulation at the PC tip in cells from the affected individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off. Thus, loss of SMO function results in abnormal PC dynamics of key components of the Hh signaling pathway and leads to a large continuum of malformations in humans.

Alleles , Developmental Disabilities/genetics , Hedgehog Proteins/metabolism , Signal Transduction , Smoothened Receptor/genetics , Base Sequence , Child , Child, Preschool , Cilia/physiology , Female , Humans , Infant , Male , Models, Molecular , Neoplasms/genetics , Nerve Tissue Proteins , Nuclear Proteins , Pedigree , Zinc Finger Protein Gli2 , Zinc Finger Protein Gli3
Hum Mutat ; 41(8): 1372-1382, 2020 08.
Article En | MEDLINE | ID: mdl-32333448

Pathogenic variants in the core spliceosome U5 small nuclear ribonucleoprotein gene EFTUD2/SNU114 cause the craniofacial disorder mandibulofacial dysostosis Guion-Almeida type (MFDGA). MFDGA-associated variants in EFTUD2 comprise large deletions encompassing EFTUD2, intragenic deletions and single nucleotide truncating or missense variants. These variants are predicted to result in haploinsufficiency by loss-of-function of the variant allele. While the contribution of deletions within EFTUD2 to allele loss-of-function are self-evident, the mechanisms by which missense variants are disease-causing have not been characterized functionally. Combining bioinformatics software prediction, yeast functional growth assays, and a minigene (MG) splicing assay, we have characterized how MFDGA missense variants result in EFTUD2 loss-of-function. Only four of 19 assessed missense variants cause EFTUD2 loss-of-function through altered protein function when modeled in yeast. Of the remaining 15 missense variants, five altered the normal splicing pattern of EFTUD2 pre-messenger RNA predominantly through exon skipping or cryptic splice site activation, leading to the introduction of a premature termination codon. Comparison of bioinformatic predictors for each missense variant revealed a disparity amongst different software packages and, in many cases, an inability to correctly predict changes in splicing subsequently determined by MG interrogation. This study highlights the need for laboratory-based validation of bioinformatic predictions for EFTUD2 missense variants.

Am J Med Genet A ; 179(7): 1304-1309, 2019 07.
Article En | MEDLINE | ID: mdl-31004414

The spectrum of clinical consequences of variants in the Platelet derived growth factor receptor beta (PDGFRB) gene is wide. Missense variants leading to variable loss of signal transduction in vitro have been reported in the idiopathic basal ganglia calcification (IBGC) syndrome Type 4. In contrast, gain-of-function variants have been reported in infantile myofibromatosis, Penttinen syndrome, and Kosaki overgrowth syndrome. Here, we report a patient harboring a novel postzygotic variant in PDGFRB (c.1682_1684del, p.[Arg561_Tyr562delinsHis]) and presenting severe cerebral malformations, intracerebral calcifications, and infantile myofibromatosis. This observation expands the phenotype associated with PDGFRB variants and illustrates the wide clinical spectrum linked to dysregulation of PDGFRB.

Brain/abnormalities , Calcinosis/genetics , Myofibromatosis/genetics , Receptor, Platelet-Derived Growth Factor beta/genetics , Brain/diagnostic imaging , Female , Humans , Infant, Newborn , Magnetic Resonance Imaging , Male , Mutation, Missense
Am J Hum Genet ; 104(3): 530-541, 2019 03 07.
Article En | MEDLINE | ID: mdl-30827496

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

Adaptor Proteins, Signal Transducing/genetics , Autistic Disorder/etiology , Intellectual Disability/etiology , Mutation, Missense , Nuclear Proteins/genetics , Adolescent , Adult , Amino Acid Sequence , Autistic Disorder/metabolism , Autistic Disorder/pathology , Child , Child, Preschool , Female , Genetic Association Studies , Humans , Infant , Intellectual Disability/metabolism , Intellectual Disability/pathology , Male , Prognosis , Sequence Homology , Syndrome , Young Adult
Am J Hum Genet ; 104(2): 319-330, 2019 02 07.
Article En | MEDLINE | ID: mdl-30639322

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.

Developmental Disabilities/genetics , Intellectual Disability/genetics , Point Mutation , Transcription Factors/genetics , Alleles , Animals , Child , Child, Preschool , Developmental Disabilities/pathology , Female , Humans , Infant , Intellectual Disability/pathology , Male , Mice , Syndrome , Transcription Factors/chemistry , Transcription Factors/metabolism
Am J Hum Genet ; 104(1): 139-156, 2019 01 03.
Article En | MEDLINE | ID: mdl-30595372

Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Cα subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(δ) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.

Intellectual Disability/genetics , Mutation , Protein Phosphatase 2/genetics , Adolescent , Child , Child, Preschool , DNA Mutational Analysis , Female , HEK293 Cells , Haploinsufficiency/genetics , Humans , Male , Protein Binding/genetics , Protein Subunits/chemistry , Protein Subunits/metabolism , Syndrome
Nucleic Acids Res ; 47(6): 2822-2839, 2019 04 08.
Article En | MEDLINE | ID: mdl-30698748

The DNA methylation epigenetic signature is a key determinant during development. Rules governing its establishment and maintenance remain elusive especially at repetitive sequences, which account for the majority of methylated CGs. DNA methylation is altered in a number of diseases including those linked to mutations in factors that modify chromatin. Among them, SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain Containing 1) has been of major interest following identification of germline mutations in Facio-Scapulo-Humeral Dystrophy (FSHD) and in an unrelated developmental disorder, Bosma Arhinia Microphthalmia Syndrome (BAMS). By investigating why germline SMCHD1 mutations lead to these two different diseases, we uncovered a role for this factor in de novo methylation at the pluripotent stage. SMCHD1 is required for the dynamic methylation of the D4Z4 macrosatellite upon reprogramming but seems dispensable for methylation maintenance. We find that FSHD and BAMS patient's cells carrying SMCHD1 mutations are both permissive for DUX4 expression, a transcription factor whose regulation has been proposed as the main trigger for FSHD. These findings open new questions as to what is the true aetiology for FSHD, the epigenetic events associated with the disease thus calling the current model into question and opening new perspectives for understanding repetitive DNA sequences regulation.

Chromosomal Proteins, Non-Histone/physiology , DNA Methylation , Homeodomain Proteins/genetics , Microsatellite Repeats/genetics , Cells, Cultured , Cellular Reprogramming/genetics , Choanal Atresia/genetics , Choanal Atresia/metabolism , DNA Methylation/genetics , Epigenesis, Genetic/genetics , Gene Expression Regulation , HCT116 Cells , HEK293 Cells , Homeodomain Proteins/metabolism , Humans , Male , Microphthalmos/genetics , Microphthalmos/metabolism , Muscular Dystrophy, Facioscapulohumeral/genetics , Muscular Dystrophy, Facioscapulohumeral/metabolism , Muscular Dystrophy, Facioscapulohumeral/pathology , Nose/abnormalities
Nat Commun ; 9(1): 3087, 2018 08 06.
Article En | MEDLINE | ID: mdl-30082715

Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7-/- mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7-/- mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development.

Amelogenesis Imperfecta/genetics , Bone Diseases, Developmental/genetics , Mutation , Organic Anion Transporters, Sodium-Dependent/genetics , Symporters/genetics , Animals , Body Weight , COS Cells , Child , Child, Preschool , Chlorocebus aethiops , Disease Models, Animal , Electrophoresis , Exome , Glycoproteins/chemistry , HEK293 Cells , Humans , Infant , Mice , Mice, Knockout , Osteochondrodysplasias/genetics
J Clin Endocrinol Metab ; 103(11): 4023-4032, 2018 11 01.
Article En | MEDLINE | ID: mdl-30137364

Context: Most cases of autosomal dominant isolated hypoparathyroidism are caused by gain-of-function mutations in CASR or GNA11 or dominant negative mutations in GCM2 or PTH. Objective: To identify the genetic etiology for dominantly transmitted isolated hypoparathyroidism in two multigenerational families with 14 affected family members. Methods: We performed whole exome sequencing of DNA from two families and examined the consequences of mutations by minigene splicing assay. Results: We discovered disease-causing mutations in both families. A splice-altering mutation in TBX1 (c.1009+1G>C) leading to skipping of exon 8 (101 bp) was identified in 10 affected family members and five unaffected subjects of family A, indicating reduced penetrance for this point mutation. In a second family from France (family B), we identified another splice-altering mutation (c.1009+2T>C) adjacent to the mutation identified in family A that results in skipping of the same exon; two subjects in family B had isolated hypoparathyroidism, whereas a third subject manifested the clinical triad of the 22q11.2 deletion syndrome, indicative of variable expressivity. Conclusions: We report evidence that heterozygous TBX1 mutations can cause isolated hypoparathyroidism. This study adds knowledge to the increasingly expanding list of causative and candidate genes in isolated hypoparathyroidism.

DiGeorge Syndrome/genetics , Hypercalciuria/genetics , Hypocalcemia/genetics , Hypoparathyroidism/congenital , T-Box Domain Proteins/genetics , Aged , DiGeorge Syndrome/blood , DiGeorge Syndrome/diagnosis , Exons/genetics , Female , Heterozygote , Humans , Hypercalciuria/blood , Hypercalciuria/diagnosis , Hypocalcemia/blood , Hypocalcemia/diagnosis , Hypoparathyroidism/blood , Hypoparathyroidism/diagnosis , Hypoparathyroidism/genetics , Infant , Male , Mutation , Pedigree , Penetrance , RNA Splice Sites/genetics , Whole Exome Sequencing
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 Dysmorphol ; 27(2): 31-35, 2018 Apr.
Article En | MEDLINE | ID: mdl-29381487

Mandibulofacial dysostosis type Guion-Almeida (MFDGA) is a rare disease entity that results in congenital craniofacial anomalies that are caused by abnormal development of the first and second pharyngeal arches. MFDGA is characterized by malar and mandibular hypoplasia, microcephaly, developmental delay, dysplastic ears, and a distinctive facial appearance. Extracraniofacial malformations include esophageal atresia, congenital heart disease, and radial ray abnormalities. Heterozygous mutations in the elongation factor Tu GTP-binding domain containing 2 (EFTUD2) gene have been shown to result in MFDGA. To date, there have been a total of 108 individuals reported in the literature, of whom 95 patients have a confirmed EFTUD2 mutation. The majority of individuals reported in the literature have been of White ethnic origin. Here, we report two individuals of Asian ancestry with MFDGA, each harboring a novel, pathogenic splice site variant in EFTUD2.

Developmental Disabilities/genetics , Mandibulofacial Dysostosis/genetics , Peptide Elongation Factors/genetics , Ribonucleoprotein, U5 Small Nuclear/genetics , Child, Preschool , Developmental Disabilities/physiopathology , Female , Heterozygote , Humans , Infant , Male , Mandibulofacial Dysostosis/physiopathology , Mutation , Protein Isoforms/genetics
Eur J Hum Genet ; 26(3): 340-349, 2018 03.
Article En | MEDLINE | ID: mdl-29330547

Fryns syndrome (FS) is a multiple malformations syndrome with major features of congenital diaphragmatic hernia, pulmonary hypoplasia, craniofacial dysmorphic features, distal digit hypoplasia, and a range of other lower frequency malformations. FS is typically lethal in the fetal or neonatal period. Inheritance is presumed autosomal recessive. Although no major genetic cause has been identified for FS, biallelic truncating variants in PIGN, encoding a component of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, have been identified in a limited number of cases with a phenotype compatible with FS. Biallelic variants in PIGN, typically missense or compound missense with truncating, also cause multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Here we report six further patients with FS with or without congenital diaphragmatic hernia and recessive loss of function PIGN alleles, including an intragenic deletion with a likely founder effect in La Réunion and other Indian Ocean islands. Our results support the hypothesis that a spectrum of phenotypic severity is associated with recessive PIGN variants, ranging from FS at the extreme end, caused by complete loss of function, to MCAHS1, in which some residual PIGN function may remain. Our data add FS resulting from PIGN variants to the catalog of inherited GPI deficiencies caused by the disruption of the GPI-anchor biosynthesis pathway.

Founder Effect , Hernia, Diaphragmatic/genetics , Limb Deformities, Congenital/genetics , Loss of Function Mutation , Phosphotransferases/genetics , Facies , Female , Gene Deletion , Hernia, Diaphragmatic/pathology , Humans , Infant , Infant, Newborn , Limb Deformities, Congenital/pathology , Male