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1.
Am J Hum Genet ; 109(8): 1421-1435, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35830857

RESUMO

PPFIBP1 encodes for the liprin-ß1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications.


Assuntos
Epilepsia , Microcefalia , Malformações do Sistema Nervoso , Transtornos do Neurodesenvolvimento , Acetilcolinesterase/genética , Animais , Drosophila melanogaster/genética , Epilepsia/genética , Perda de Heterozigosidade , Microcefalia/genética , Transtornos do Neurodesenvolvimento/genética , Linhagem
2.
J Hum Genet ; 69(6): 263-270, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38459224

RESUMO

Biallelic pathogenic variants in MADD lead to a very rare neurodevelopmental disorder which is phenotypically pleiotropic grossly ranging from severe neonatal hypotonia, failure to thrive, multiple organ dysfunction, and early lethality to a similar but milder phenotype with better survival. Here, we report 5 patients from 3 unrelated Egyptian families in whom 4 patients showed the severe end of the spectrum displaying neonatal respiratory distress, hypotonia and chronic diarrhea while one patient presented with the mild form displaying moderate intellectual disability and myopathy. In addition, we observed distal arthrogryposis and nonspecific structural brain anomalies in all our patients. Interestingly, cerebellar and brainstem hypoplasia were noted in one patient. Whole exome sequencing identified three novel homozygous variants in the MADD gene: two likely pathogenic [c.4321delC p.(Gln1441ArgfsTer46) and c.2620 C > T p.(Arg874Ter)] and one variant of uncertain significance (c.4307 G > A, p.Arg1436Gln). The variants segregated with the disease in all available family members. Our findings confirm that arthrogryposis, genital, cardiac and structural brain anomalies are manifestations of MADD which expand the spectrum of MADD-related neurodevelopmental disorder. Moreover, they further highlight the convergence of MADD variants on different organ systems leading to complex phenotypes.


Assuntos
Transtornos do Neurodesenvolvimento , Linhagem , Fenótipo , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Artrogripose/genética , Artrogripose/patologia , Encéfalo/patologia , Encéfalo/anormalidades , Egito , Sequenciamento do Exoma , Homozigoto , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Mutação , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia
3.
J Hum Genet ; 2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-39414991

RESUMO

Biallelic loss of function variants in ESAM (endothelial cell adhesion molecule) have recently been reported in 14 individuals (9 families) presenting with prenatal intracranial hemorrhage. Here, we describe four patients from two unrelated families in whom three of them presented with variable onset encephalopathy and seizures while one only displayed profound delay without seizures. Brain MRI showed variable onset intracranial hemorrhage that evolved to hydrocephalus in 3 patients, whereas hemosiderin deposits, white matter volume loss, and porencephalic cysts were noted in one patient. Unlike the majority of described cases, the youngest brother of the first family did not show microcephaly and failure to thrive. Exome sequencing identified two novel homozygous ESAM variants. A splice variant (c.731-2A>G) was identified in one family which was confirmed by investigating the patient's mRNA to result in exon skipping and early protein truncation. In addition, a missense variant (c.561G>C; p.Trp187Cys) was identified in the other family, which is the first disease causing missense variant to be described in patients with ESAM deficient phenotype. In addition, a maternally inherited pathogenic MC4R variant (c.811T>C; p.Cys271 Arg) was also identified in the youngest brother of the first family. Variants in the MC4R gene are associated with a non-syndromic form of obesity that could explain the unusual macrocephaly and obesity. Our work establishes ESAM as a tight junction gene that can present with variable neuroradiological and clinical phenotypes when mutated. Moreover, it refines the phenotype of this ultrarare syndrome and extends the number and type of variants described to date.

4.
Clin Genet ; 105(1): 92-98, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37671596

RESUMO

Pathogenic variants in PNPLA8 have been described either with congenital onset displaying congenital microcephaly, early onset epileptic encephalopathy and early lethality or childhood neurodegeneration with progressive microcephaly. Moreover, a phenotype comprising adulthood onset cerebellar ataxia and peripheral neuropathy was also reported. To our knowledge, only six patients with biallelic variants in PNPLA8 have been reported so far. Here, we report the clinical and molecular characterizations of three additional patients in whom exome sequencing identified a loss of function variant (c.1231C>T, p.Arg411Ter) in Family I and a missense variant (c.1559T>A, p.Val520Asp) in Family II in PNPLA8. Patient 1 presented with the congenital form of the disease while Patients 2 and 3 showed progressive microcephaly, infantile onset seizures, progressive cortical atrophy, white matter loss, bilateral degeneration of basal ganglia, and cystic encephalomalacia. Therefore, our results add the infantile onset as a new distinct phenotype of the disease and suggest that the site of the variant rather than its type is strongly correlated with the disease onset. In addition, these conditions demonstrate some overlapping features representing a spectrum with clinical features always aligning with different age of onset.


Assuntos
Ataxia Cerebelar , Microcefalia , Humanos , Adulto , Criança , Microcefalia/genética , Fenótipo , Ataxia Cerebelar/genética , Mutação de Sentido Incorreto , Gânglios da Base
5.
J Hum Genet ; 68(9): 607-613, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37106064

RESUMO

WLS (Wnt ligand secretion mediator or Wntless) orchestrates the secretion of all Wnt proteins, a family of evolutionary conserved proteins, involved in Wnt signaling pathway that has many essential biological functions including the regulation of development, cell proliferation, migration and apoptosis. Biallelic variants in WLS have recently been described in 10 patients with pleiotropic multiple congenital anomalies (MCA) known as Zaki syndrome. We identified a likely disease-causing variant in WLS (c.1579G>A, p.Gly527Arg) in a boy presented with a broad range of MCA including microcephaly, facial dysmorphism, alopecia, ophthalmologic anomalies, and complete soft tissue syndactyly. These features were reminiscent of Zaki syndrome although variable clinical severity was observed. In a detailed clinical assessment, our patient also displayed microphthalmia, dental anomalies, skeletal dysplasia with spontaneous fractures and Dandy-Walker malformation. As such, we extend the phenotype linked to Zaki syndrome. This study further highlights the importance of a thorough clinical evaluation to delineate the phenotypic spectrum associated with WLS variants and suggests that genotype-phenotype correlations due to variant localization seems likely. However, future work on additional patients and more functional studies may give further insights into genotype-phenotype correlations and the complex function of WLS.


Assuntos
Receptores Acoplados a Proteínas G , Apoptose , Fenótipo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Wnt/genética , Via de Sinalização Wnt/genética , Humanos
6.
Clin Genet ; 104(3): 356-364, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37190898

RESUMO

Biallelic variants in PPIL1 have been recently found to cause a very rare type of pontocerebellar hypoplasia and congenital microcephaly in which simplified gyral pattern was not observed in all of the patients. Here, we describe a series of nine patients from eight unrelated Egyptian families in whom whole exome sequencing detected a previously reported homozygous missense variant (c.295G>A, p.Ala99Thr) in PPIL1. Haplotype analysis confirmed that this variant has a founder effect in our population. All our patients displayed early onset drug-resistant epilepsy, profound developmental delay, and visual impairment. Remarkably, they presented with recognizable imaging findings showing profound microcephaly, hypoplastic frontal lobe and posteriorly predominant pachygyria, agenesis of corpus callosum with colpocephaly, and pontocerebellar hypoplasia. In addition, Dandy-Walker malformation was evident in three patients. Interestingly, four of our patients exhibited hematopoietic disorder (44% of cases). We compared the phenotype of our patients with other previously reported PPIL1 patients. Our results reinforce the hypothesis that the alterative splicing of PPIL1 causes a heterogeneous phenotype. Further, we affirm that hematopoietic disorder is a common feature of the condition and underscore the role of major spliceosomes in brain development.


Assuntos
Encefalopatias , Doenças Cerebelares , Síndrome de Dandy-Walker , Microcefalia , Humanos , Microcefalia/diagnóstico por imagem , Microcefalia/genética , Doenças Cerebelares/genética , Peptidilprolil Isomerase
7.
Am J Med Genet A ; 191(8): 2100-2112, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37183573

RESUMO

Biallelic variants in CHST3 gene result in congenital dislocation of large joints, club feet, short stature, rhizomelia, kypho-scoliosis, platyspondyly, epiphyseal dysplasia, flared metaphysis, in addition to minor cardiac lesions and hearing loss. Herein, we describe 14 new patients from 11 unrelated Egyptian families with CHST3-related skeletal dysplasia. All patients had spondyloepiphyseal changes that were progressive with age in addition to bifid distal ends of humeri which can be considered a diagnostic key in patients with CHST3 variants. They also shared peculiar facies with broad forehead, broad nasal tip, long philtrum and short neck. Rare unusual associated findings included microdontia, teeth spacing, delayed eruption, prominent angulation of the lumbar-sacral junction and atrial septal defect. Mutational analysis revealed 10 different homozygous CHST3 (NM_004273.5) variants including 7 missense, two frameshift and one nonsense variant. Of them, the c.384_391dup (p.Pro131Argfs*88) was recurrent in two families. Eight of these variants were not described before. Our study presents the largest series of patients with CHST3-related skeletal dysplasia from the same ethnic group. Furthermore, it reinforces that lethal cardiac involvement is a critical clinical finding of the disorder. Therefore, we believe that our study expands the phenotypic and mutational spectrum, and also highlights the importance of performing echocardiography in patients harboring CHST3 variants.


Assuntos
Nanismo , Osteocondrodisplasias , Humanos , Nanismo/diagnóstico por imagem , Nanismo/genética , Homozigoto , Mutação , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Carboidrato Sulfotransferases
8.
Brain ; 145(4): 1551-1563, 2022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34694367

RESUMO

The major spliceosome mediates pre-mRNA splicing by recognizing the highly conserved sequences at the 5' and 3' splice sites and the branch point. More than 150 proteins participate in the splicing process and are organized in the spliceosomal A, B, and C complexes. FRA10AC1 is a peripheral protein of the spliceosomal C complex and its ortholog in the green alga facilitates recognition or interaction with splice sites. We identified biallelic pathogenic variants in FRA10AC1 in five individuals from three consanguineous families. The two unrelated Patients 1 and 2 with loss-of-function variants showed developmental delay, intellectual disability, and no speech, while three siblings with the c.494_496delAAG (p.Glu165del) variant had borderline to mild intellectual disability. All patients had microcephaly, hypoplasia or agenesis of the corpus callosum, growth retardation, and craniofacial dysmorphism. FRA10AC1 transcripts and proteins were drastically reduced or absent in fibroblasts of Patients 1 and 2. In a heterologous expression system, the p.Glu165del variant impacts intrinsic stability of FRA10AC1 but does not affect its nuclear localization. By co-immunoprecipitation, we found ectopically expressed HA-FRA10AC1 in complex with endogenous DGCR14, another component of the spliceosomal C complex, while the splice factors CHERP, NKAP, RED, and SF3B2 could not be co-immunoprecipitated. Using an in vitro splicing reporter assay, we did not obtain evidence for FRA10AC1 deficiency to suppress missplicing events caused by mutations in the highly conserved dinucleotides of 5' and 3' splice sites in an in vitro splicing assay in patient-derived fibroblasts. Our data highlight the importance of specific peripheral spliceosomal C complex proteins for neurodevelopment. It remains possible that FRA10AC1 may have other and/or additional cellular functions, such as coupling of transcription and splicing reactions.


Assuntos
Transtornos do Crescimento , Deficiência Intelectual , Microcefalia , Transtornos do Neurodesenvolvimento , Proteínas Nucleares , Proteínas de Ligação a DNA/genética , Transtornos do Crescimento/genética , Humanos , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Microcefalia/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Nucleares/genética , Sítios de Splice de RNA , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/genética
9.
J Hum Genet ; 67(11): 669-673, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35896821

RESUMO

Developmental brain malformations are rare but are increasingly reported features of BICD2-related disorders. Here, we report a 2-year old boy with microcephaly, profound delay and partial seizures. His brain MRI showed lissencephaly, hypogenesis of corpus callosum, dysplastic hipocampus and cerebellar hypoplasia. Whole-exome sequencing identified a novel homozygous likely pathogenic variant in the BICD2 gene, c.229 C > T p.(Gln77Ter). This is the first report of lissencephaly and cerebellar hypoplasia seen in a patient with homozygous loss-of-function variant in BICD2 that recapitulated the animal model. Our report supports that BICD2 should be considered in the differential diagnosis for patients with lissencephaly and cerebellar hypoplasia Additional clinical features of BICD2 are likely to emerge with the identification of additional patients.


Assuntos
Lisencefalia , Microcefalia , Malformações do Sistema Nervoso , Animais , Criança , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Lisencefalia/diagnóstico por imagem , Lisencefalia/genética , Cerebelo/patologia , Deficiências do Desenvolvimento/genética , Microcefalia/diagnóstico por imagem , Microcefalia/genética , Microcefalia/patologia
10.
J Hum Genet ; 67(1): 55-64, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34354232

RESUMO

Biallelic pathogenic variants of OTUD6B have recently been described to cause intellectual disability (ID) with seizures. Here, we report the clinical and molecular characterization of five additional patients (from two unrelated Egyptian families) with ID due to homozygous OTUD6B variants. In Family I, the two affected brothers had additional retinal degeneration, a symptom not yet reported in OTUD6B-related ID. Whole-exome sequencing (WES) identified a novel nonsense variant in OTUD6B (c.271C>T, p.(Gln91Ter)), but also a nonsense variant in RP1L1 (c.5959C>T, p.(Gln1987Ter)), all in homozygous state. Biallelic pathogenic variants in RP1L1 cause autosomal recessive retinitis pigmentosa type 88 (RP88). Thus, RP1L1 dysfunction likely accounts for the visual phenotype in this family with two simultaneous autosomal recessive disorders. In Family II, targeted sequencing revealed a novel homozygous missense variant (c.767G>T, p.(Gly256Val)), confirming the clinically suspected OTUD6B-related ID. Consistent with the clinical variability in previously reported OTUD6B patients, our patients showed inter- and intrafamilial differences with regard to the clinical and brain imaging findings. Interestingly, various orodental features were present including macrodontia, dental crowding, abnormally shaped teeth, and thick alveolar ridges. Broad distal phalanges (especially the thumbs and halluces) with prominent interphalangeal joints and fetal pads were recognized in all patients and hence considered pathognomonic. Our study extends the spectrum of the OTUD6B-associated phenotype. Retinal degeneration, albeit present in both patients from Family I, was shown to be unrelated to OTUD6B, demonstrating the need for in-depth analysis of WES data in consanguineous families to uncover simultaneous autosomal recessive disorders.


Assuntos
Endopeptidases/genética , Predisposição Genética para Doença , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Mutação , Fenótipo , Alelos , Estudos de Associação Genética , Genótipo , Humanos , Degeneração Retiniana/genética , Sequenciamento do Exoma
11.
Clin Genet ; 101(5-6): 530-540, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35322404

RESUMO

Homozygous pathogenic variants in WDR45B were first identified in six subjects from three unrelated families with global development delay, refractory seizures, spastic quadriplegia, and brain malformations. Since the initial report in 2018, no further cases have been described. In this report, we present 12 additional individuals from seven unrelated families and their clinical, radiological, and molecular findings. Six different variants in WDR45B were identified, five of which are novel. Microcephaly and global developmental delay were observed in all subjects, and seizures and spastic quadriplegia in most. Common findings on brain imaging include cerebral atrophy, ex vacuo ventricular dilatation, brainstem volume loss, and symmetric under-opercularization. El-Hattab-Alkuraya syndrome is associated with a consistent phenotype characterized by early onset cerebral atrophy resulting in microcephaly, developmental delay, spastic quadriplegia, and seizures. The phenotype appears to be more severe among individuals with loss-of-function variants whereas those with missense variants were less severely affected suggesting a potential genotype-phenotype correlation in this disorder. A brain imaging pattern emerges which is consistent among individuals with loss-of-function variants and could potentially alert the neuroradiologists or clinician to consider WDR45B-related El-Hattab-Alkuraya syndrome.


Assuntos
Microcefalia , Malformações do Sistema Nervoso , Atrofia , Doenças Ósseas Metabólicas , Defeitos Congênitos da Glicosilação , Homozigoto , Humanos , Microcefalia/diagnóstico por imagem , Microcefalia/genética , Microcefalia/patologia , Linhagem , Fenótipo , Quadriplegia/genética , Convulsões/diagnóstico por imagem , Convulsões/genética
12.
Acta Neuropathol ; 143(2): 245-262, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34918187

RESUMO

Nucleotide metabolism is a complex pathway regulating crucial cellular processes such as nucleic acid synthesis, DNA repair and proliferation. This study shows that impairment of the biosynthesis of one of the building blocks of DNA, dTTP, causes a severe, early-onset neurodegenerative disease. Here, we describe two unrelated children with bi-allelic variants in DTYMK, encoding dTMPK, which catalyzes the penultimate step in dTTP biosynthesis. The affected children show severe microcephaly and growth retardation with minimal neurodevelopment. Brain imaging revealed severe cerebral atrophy and disappearance of the basal ganglia. In cells of affected individuals, dTMPK enzyme activity was minimal, along with impaired DNA replication. In addition, we generated dtymk mutant zebrafish that replicate this phenotype of microcephaly, neuronal cell death and early lethality. An increase of ribonucleotide incorporation in the genome as well as impaired responses to DNA damage were observed in dtymk mutant zebrafish, providing novel pathophysiological insights. It is highly remarkable that this deficiency is viable as an essential component for DNA cannot be generated, since the metabolic pathway for dTTP synthesis is completely blocked. In summary, by combining genetic and biochemical approaches in multiple models we identified loss-of-function of DTYMK as the cause of a severe postnatal neurodegenerative disease and highlight the essential nature of dTTP synthesis in the maintenance of genome stability and neuronal survival.


Assuntos
Doenças Neurodegenerativas/genética , Núcleosídeo-Fosfato Quinase/genética , Animais , Feminino , Humanos , Masculino , Microcefalia/genética , Mutação , Peixe-Zebra
13.
Am J Med Genet A ; 188(2): 648-657, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34761517

RESUMO

SMG8 (MIM *617315) is a regulatory subunit involved in nonsense-mediated mRNA decay (NMD), a cellular protective pathway that regulates mRNA transcription, transcript stability, and degrades transcripts containing premature stop codons. SMG8 binds SMG9 and SMG1 to form the SMG1C complex and inhibit the kinase activity of SMG1. Biallelic deleterious variants in SMG9 are known to cause a heart and brain malformation syndrome (HBMS; MIM #616920), whereas biallelic deleterious variants in SMG8 were recently described to cause a novel neurodevelopmental disorder (NDD) with dysmorphic facies and cataracts, now defined as Alzahrani-Kuwahara syndrome (ALKUS: MIM #619268). Only eight subjects from four families with ALKUS have been described to date. Through research reanalysis of a nondiagnostic clinical exome, we identified a subject from a fifth unrelated family with a homozygous deleterious variant in SMG8 and features consistent with ALKUS. Interestingly, the subject also had unilateral microphthalmia, a clinical feature that has been described in SMG9-related disorder. Our study expands the phenotypic spectrum of SMG8-related disorder, demonstrates an overlapping phenotype between SMG8- and SMG9-related rare disease traits, provides further evidence for the SMG8 and SMG9 protein interactions, and highlights the importance of revisiting nondiagnostic exome data to identify and affirm emerging novel genes for rare disease traits.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular , Degradação do RNAm Mediada por Códon sem Sentido , Alelos , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fenótipo , Fosforilação
14.
Am J Med Genet A ; 188(3): 735-750, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34816580

RESUMO

Genomic sequencing and clinical genomics have demonstrated that substantial subsets of atypical and/or severe disease presentations result from multilocus pathogenic variation (MPV) causing blended phenotypes. In an infant with a severe neurodevelopmental disorder, four distinct molecular diagnoses were found by exome sequencing (ES). The blended phenotype that includes brain malformation, dysmorphism, and hypotonia was dissected using the Human Phenotype Ontology (HPO). ES revealed variants in CAPN3 (c.259C > G:p.L87V), MUSK (c.1781C > T:p.A594V), NAV2 (c.1996G > A:p.G666R), and ZC4H2 (c.595A > C:p.N199H). CAPN3, MUSK, and ZC4H2 are established disease genes linked to limb-girdle muscular dystrophy (OMIM# 253600), congenital myasthenia (OMIM# 616325), and Wieacker-Wolff syndrome (WWS; OMIM# 314580), respectively. NAV2 is a retinoic-acid responsive novel disease gene candidate with biological roles in neurite outgrowth and cerebellar dysgenesis in mouse models. Using semantic similarity, we show that no gene identified by ES individually explains the proband phenotype, but rather the totality of the clinically observed disease is explained by the combination of disease-contributing effects of the identified genes. These data reveal that multilocus pathogenic variation can result in a blended phenotype with each gene affecting a different part of the nervous system and nervous system-muscle connection. We provide evidence from this n = 1 study that in patients with MPV and complex blended phenotypes resulting from multiple molecular diagnoses, quantitative HPO analysis can allow for dissection of phenotypic contribution of both established disease genes and novel disease gene candidates not yet proven to cause human disease.


Assuntos
Distrofia Muscular do Cíngulo dos Membros , Transtornos do Neurodesenvolvimento , Animais , Calpaína/genética , Egito , Humanos , Lactente , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Sequenciamento do Exoma
15.
Neurogenetics ; 22(4): 287-295, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34338917

RESUMO

Fetal brain arrest is an extremely rare genetic disorder that was described in few patients and encompasses very unique findings of underdeveloped cerebral hemispheres in association with collapsed skull bones. Based on the recurrence among sibs, an autosomal recessive mode of inheritance was proposed; however, no causative gene was identified so far. Here, we report the identification of biallelic variants in the WDR81 gene in two unrelated families (4 patients) with fetal brain arrest including the originally described family and an additional new family. Two homozygous variants were identified: a new missense (c.1157 T > C, p.Val386Ala) and a previously described frameshift variant, c.4668_4669delAG (p.Gly1557AspfsTer16). We assessed the expression of WDR81 at the protein level by western blot analysis using primary skin fibroblast cultures established from the patient with the missense variant and noticed that WDR81 expression was significantly reduced in comparison to normal control confirming the pathogenicity of this variant. Our findings confirm the involvement of WDR81 in the pathogenesis of fetal brain arrest syndrome and suggest that fetal brain arrest represents the severe end of the spectrum phenotypes caused by pathogenic variants in WDR81. In addition, we reviewed the clinical and molecular data on WDR81-related disorders and phenotype/genotype correlations.


Assuntos
Encefalopatias/genética , Encéfalo/patologia , Proteínas do Tecido Nervoso/genética , Encéfalo/anormalidades , Encefalopatias/patologia , Homozigoto , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Fenótipo
16.
Am J Med Genet A ; 185(12): 3728-3739, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34346154

RESUMO

Kinesin super family (KIF) genes encode motor kinesins, a family of evolutionary conserved proteins, involved in intracellular trafficking of various cargoes. These proteins are critical for various physiological processes including neuron function and survival, ciliary function and ciliogenesis, and cell-cycle progression. Recent evidence suggests that alterations in motor kinesin genes can lead to a variety of human diseases, including monogenic disorders. Neuropathies, impaired higher brain functions, structural brain abnormalities and multiple congenital anomalies (i.e., renal, urogenital, and limb anomalies) can result from pathogenic variants in many KIF genes. We expand the phenotype associated with KIF4A variants from developmental delay and intellectual disability with or without epilepsy to a congenital anomaly phenotype with hydrocephalus and various brain anomalies at the more severe end of phenotypic manifestations. Additional anomalies of the kidneys and urinary tract, congenital lymphedema, eye, and dental anomalies seem to be variably associated and overlap with clinical signs observed in other kinesinopathies. Caution still applies to missense variants, but hopefully, future work will further establish genotype-phenotype correlations in a larger number of patients and functional studies may give further insights into the complex function of KIF4A.


Assuntos
Anormalidades Múltiplas/genética , Encéfalo/metabolismo , Cinesinas/genética , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Anormalidades Múltiplas/patologia , Encéfalo/anormalidades , Encéfalo/patologia , Epilepsia/genética , Epilepsia/patologia , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Neurônios/metabolismo , Neurônios/patologia , Fenótipo , Anormalidades Urogenitais/patologia , Refluxo Vesicoureteral/patologia
17.
Neuropediatrics ; 52(3): 201-207, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33271615

RESUMO

Here we report a consanguineous Egyptian family with two siblings presented with congenital microcephaly, early-onset epileptic encephalopathy, feeding difficulties, and early lethality. The condition was initially diagnosed as molybdenum cofactor deficiency as the brain imaging for one of them showed brain edema and intracranial hemorrhage in addition to the hypoplastic corpus callosum, vermis hypoplasia, and small-sized pons. Subsequently, whole exome sequencing identified a novel homozygous missense variant in exon 4 of ASNS gene c.397_398GT > CA (p.Val133Gln) confirming the diagnosis of asparagine synthetase deficiency syndrome. No discernible alternative cause for the intracranial hemorrhage was found. Our patient is the second to show asparagine synthetase deficiency and intracranial hemorrhage, thus confirming the involvement of ASNS gene. As such, it is important to consider asparagine synthetase deficiency syndrome in patients with microcephaly, brain edema, and neonatal intracranial hemorrhage.


Assuntos
Aspartato-Amônia Ligase , Erros Inatos do Metabolismo dos Metais , Microcefalia , Humanos , Recém-Nascido , Hemorragias Intracranianas/etiologia , Hemorragias Intracranianas/genética , Microcefalia/genética
18.
Cytogenet Genome Res ; 160(3): 124-133, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32187602

RESUMO

Trisomy 14 is incompatible with live, but there are several patients reported with mosaic trisomy 14. We aimed to study the pattern of X inactivation and its effect on a translocated autosome and to find out an explanation of the involvement of chromosome 14 in 2 different structural chromosomal abnormalities. We report on a girl with frontal bossing, hypertelorism, low-set ears, micrognathia, cleft palate, congenital heart disease, and abnormal skin pigmentations. The patient displayed iris, choroidal, and retinal coloboma and agenesis of the corpus callosum and cerebellar vermis hypoplasia. Cytogenetic analysis revealed a karyotype 45,X,der(X)t(X;14)(q24;q11)[85]/46,XX,rob(14;14)(q10;q10),+14[35]. Array-CGH for blood and buccal mucosa showed high mosaic trisomy 14 and an Xq deletion. MLPA detected trisomy 14 in blood and buccal mucosa and also showed normal methylation of the imprinting center. FISH analysis confirmed the cell line with trisomy 14 (30%) and demonstrated the mosaic deletion of the Xq subtelomere in both tissues. There was 100% skewed X inactivation for the t(X;14). SNP analysis of the patient showed no region of loss of heterozygosity on chromosome 14. Also, genotype call analysis of the patient and her parents showed heterozygous alleles of chromosome 14 with no evidence of uniparental disomy. Our patient had a severe form of mosaic trisomy 14. We suggest that this cytogenetic unique finding that involved 2 cell lines with structural abnormalities of chromosome 14 occurred in an early postzygotic division. These 2 events may have happened separately or maybe there is a kind of trisomy or monosomy rescue due to dynamic cytogenetic interaction between different cell lines to compensate for gene dosage.


Assuntos
Anormalidades Múltiplas/genética , Trissomia/genética , Inativação do Cromossomo X/genética , Anormalidades Múltiplas/fisiopatologia , Pré-Escolar , Cromossomos Humanos Par 14/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Cariotipagem , Mosaicismo , Fenótipo , Translocação Genética/genética , Trissomia/fisiopatologia
19.
Am J Med Genet A ; 182(6): 1309-1312, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32222090

RESUMO

KBG syndrome is an intellectual disability (ID) associated with multiple congenital anomalies in which the macrodontia could be the clue for the diagnosis. It is caused either by heterozygous variant in ANKRD11 gene or 16q24.3 microdeletions that involve the ANKRD11 gene. Here, we report on two unrelated male patients who presented with ID, short stature, webbing of neck, and cryptorchidism. Noonan syndrome was suspected first but the presence of macrodontia in both patients pointed to KBG syndrome which was confirmed thereafter by the identification of a novel pathogenic variant in ANKRD11 gene, c.5488G>T (p.E1830*). Macrodontia was noticed in all the deciduous anterior teeth in Patient 1. This observation was reported previously in few patients, but it seems to be a common feature that could be misdiagnosed as premature eruption of teeth. Therefore, our results confirm that maxillary permanent central incisors may not be the only teeth affected in KBG but also all the deciduous teeth. Interestingly, desquamative gingivitis was additionally noted in Patient 1, which has not been reported previously, however; it could be a coincidental finding. To the best of our knowledge, this is the first report from Egypt.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Deleção Cromossômica , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/patologia , Adolescente , Doenças do Desenvolvimento Ósseo/patologia , Pré-Escolar , Hibridização Genômica Comparativa , Criptorquidismo/genética , Criptorquidismo/patologia , Nanismo/genética , Nanismo/patologia , Egito/epidemiologia , Fácies , Heterozigoto , Humanos , Deficiência Intelectual/patologia , Masculino , Fenótipo , Anormalidades Dentárias/patologia
20.
Am J Med Genet A ; 182(6): 1407-1420, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32267100

RESUMO

PCNT encodes a large coiled- protein localizing to pericentriolar material and is associated with microcephalic osteodysplastic primordial dwarfism type II syndrome (MOPD II). We report our experience of nine new patients from seven unrelated consanguineous Egyptian families with the distinctive clinical features of MOPD II in whom a customized NGS panel showed homozygous truncating variants of PCNT. The NGS panel results were validated thereafter using Sanger sequencing revealing three previously reported and three novel PCNT pathogenic variants. The core phenotype appeared homogeneous to what had been reported before although patients differed in the severity showing inter and intra familial variability. The orodental pattern showed atrophic alveolar ridge (five patients), rootless tooth (four patients), tooth agenesis (three patients), and malformed tooth (three patients). In addition, mesiodens was a novel finding found in one patient. The novel c.9394-1G>T variant was found in two sibs who had tooth agenesis. CNS anomalies with possible vascular sequelae were documented in two male patients (22.2%). Simplified gyral pattern with poor development of the frontal horns of lateral ventricles was seen in four patients and mild thinning of the corpus callosum in two patients. Unilateral coronal craniosynstosis was noted in one patient and thick but short corpus callosum was an unusual finding noted in another. The later has not been reported before. Our results refine the clinical, neuroradiological, and orodental features and expand the molecular spectrum of MOPD II.


Assuntos
Antígenos/genética , Nanismo/epidemiologia , Nanismo/genética , Retardo do Crescimento Fetal/epidemiologia , Retardo do Crescimento Fetal/genética , Predisposição Genética para Doença , Microcefalia/epidemiologia , Microcefalia/genética , Osteocondrodisplasias/epidemiologia , Osteocondrodisplasias/genética , Adolescente , Criança , Pré-Escolar , Consanguinidade , Nanismo/complicações , Nanismo/patologia , Egito/epidemiologia , Feminino , Retardo do Crescimento Fetal/patologia , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Microcefalia/complicações , Microcefalia/patologia , Mutação , Osteocondrodisplasias/complicações , Osteocondrodisplasias/patologia , Fenótipo , Irmãos
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