Abstract Background The 17p13.3 deletion syndrome (or Miller-Dieker syndrome, MDS, MIM 247200) is characterized by lissencephaly, mental retardation and facial dysmorphism. The phenotype is ...attributed to haploinsufficiency of two genes present in the minimal critical region of MDS: PAFAH1B1 (formerly referred to as LIS1 ) and YWHAE . Whereas isolated PAFAH1B1 deletion causes lissencephaly, YWHAE is a candidate for the dysmorphic phenotype associated with MDS. Objective We describe clinical, neuroradiological and molecular data in four patients with a 17p13.3 deletion distal to PAFAH1B1 involving YWHAE. Results All patients presented with mild or moderate developmental delay and pre and/or post-natal growth retardation. Patients A, B and C had neuro-imaging anomalies: leucoencephalopathy with macrocephaly (patients A and C), Chiari type 1 malformation (patient A) and paraventricular cysts (patient C). Patient B had patent ductus arteriosus and pulmonary arterial hypertension. Patient C had unilateral club foot. Patient D had enlarged Virchow Robin spaces, microcornea, and chorioretinal and lens coloboma. Array-CGH revealed de novo terminal 17p13.3 deletions for patient A and B, and showed interstitial 17p13.3 deletions of 1.4 Mb for patient C and of 0.5 Mb for patient D. In all patients, PAFAH1B1 was not deleted. Conclusion Our patients confirm that 17p deletion distal to PAFAH1B1 have a distinctive phenotype : mild mental retardation, moderate to severe growth restriction, white matter abnormalities and developmental defects including Chiari type 1 malformation and coloboma. Our patients contribute to the delineation and clinical characterization of 17p13.3 deletion distal to PAFAH1B1 and highlight the role of the region containing YWHAE in brain and eye development and in somatic growth.
In 65 patients, who had unexplained ocular developmental anomalies (ODAs) with at least one other birth defect and/or intellectual disability, we performed oligonucleotide comparative genome ...hybridisation-based microarray analysis (array-CGH; 105A or 180K, Agilent Technologies). In four patients, array-CGH identified clinically relevant deletions encompassing a gene known to be involved in ocular development (FOXC1 or OTX2). In four other patients, we found three pathogenic deletions not classically associated with abnormal ocular morphogenesis, namely, del(17)(p13.3p13.3), del(10)(p14p15.3), and del(16)(p11.2p11.2). We also detected copy number variations of uncertain pathogenicity in two other patients. Rearranged segments ranged in size from 0.04 to 5.68 Mb. These results show that array-CGH provides a high diagnostic yield (15%) in patients with syndromal ODAs and can identify previously unknown chromosomal regions associated with these conditions. In addition to their importance for diagnosis and genetic counselling, these data may help identify genes involved in ocular development.
Transcriptor co‐activator factor 20 gene (TCF20) encodes a nuclear chromatin‐binding protein involved in regulation of gene expression. In human pathology, pathogenic variants or deletions in TCF20 ...were identified in patients with developmental delay, variable intellectual disability and behavioral impairment (OMIM: 618430). The shared core phenotype includes developmental delay, hypotonia, motor delay, autism spectrum disorders, neurobehavioral anomalies, neurological features such as ataxia, seizures, movement disorders, structural brain anomalies, craniofacial features and various congenital anomalies. Most pathogenic variants are loss‐of‐function variants. Duplication including TCF20 was suspected to cause a neurodevelopmental disorder (NDD) with mirror traits compared to patients with TCF20 deletions. In the present study, we report three patients from three unrelated families with NDD with a de novo duplication at 22q13.2 encompassing TCF20. We propose that the TCF20 duplication could be involved in a new 22q13.2 microduplication syndrome with high penetrance, enlarging the genotype–phenotype knowledge of TCF20‐associated NDDs.
We report three patients with a de novo 22q13.2 microduplication covering the TCF20 gene associated with syndromic neurodevelopmental disorder including developmental delay/intellectual disability, speech delay, neuropsychiatric features, nonspecific dysmorphic facial features, structural brain ophthalmologic and/or skeletal anomalies.
We report a toddler affected with Angelman syndrome and isovaleric acidemia (IVA). Such association was due to paternal uniparental isodisomy (UPD) of chromosome 15 in which the proband inherited two ...paternal copies of an IVA gene point mutation. As both diseases may have severe impact on neurodevelopment, adequate treatment of IVA should be discussed. In our patient however, the variant identified likely causes asymptomatic organic aciduria. Such findings emphasize that paternal UPD 15 can rarely lead to co-occurrence of Angelman syndrome and potentially treatable inborn errors of metabolism.
The Forkhead transcription factor FOXG1 is a prerequisite for telencephalon development in mammals and is an essential factor controlling expansion of the dorsal telencephalon by promoting neuron and ...interneuron production. Heterozygous FOXG1 gene mutations cause FOXG1 syndrome characterized by severe intellectual disability, motor delay, dyskinetic movements and epilepsy. Neuroimaging studies in patients disclose constant features including microcephaly, corpus callosum dysgenesis and delayed myelination. Currently, investigative research on the underlying pathophysiology relies on mouse models only and indicates that de-repression of FOXG1 target genes may cause premature neuronal differentiation at the expense of the progenitor pool, patterning and migration defects with impaired formation of cortico-cortical projections. It remains an open question to which extent this recapitulates the neurodevelopmental pathophysiology in FOXG1-haploinsufficient patients. To close this gap, we performed neuropathological analyses in two foetal cases with FOXG1 premature stop codon mutations interrupted during the third trimester of the pregnancy for microcephaly and corpus callosum dysgenesis. In these foetuses, we observed cortical lamination defects and decreased neuronal density mainly affecting layers II, III and V that normally give rise to cortico-cortical and inter-hemispheric axonal projections. GABAergic interneurons were also reduced in number in the cortical plate and persisting germinative zones. Additionally, we observed more numerous PDGFRα-positive oligodendrocyte precursor cells and fewer Olig2-positive pre-oligodendrocytes compared to age-matched control brains, arguing for delayed production and differentiation of oligodendrocyte lineage leading to delayed myelination. These findings provide key insights into the human pathophysiology of FOXG1 syndrome.
Juvenile myelomonocytic leukemia (JMML) is a rare, generally aggressive myeloproliferative neoplasm affecting young children. It is characterized by granulomonocytic expansion, with monocytosis ...infiltrating peripheral tissues. JMML is initiated by mutations upregulating RAS signaling. Approximately 10% of cases remain without an identified driver event. Exome sequencing of 2 unrelated cases of familial JMML of unknown genetics and analysis of the French JMML cohort identified 11 patients with variants in SH2B3, encoding LNK, a negative regulator of the JAK-STAT pathway. All variants were absent from healthy population databases, and mutation spectrum was consistent with a loss of function of the LNK protein. A stoploss variant was shown to affect both protein synthesis and stability. The other variants were either truncating or missense, the latter affecting the SH2 domain that interacts with activated JAK. Of the 11 patients, 8 from 5 families inherited pathogenic bi-allelic SH2B3 germline variants from their unaffected heterozygous parents. These children represent half of the cases with no identified causal mutation in the French cohort. They displayed typical clinical and hematological JMML features with neonatal onset and marked thrombocytopenia. They were characterized by absence of additional genetic alterations and a hypomethylated DNA profile with fetal characteristics. All patients showed partial or complete spontaneous clinical resolution. However, progression to thrombocythemia and immunity-related pathologies may be of concern later in life. Bi-allelic SH2B3 germline mutations thus define a new condition predisposing to a JMML-like disorder, suggesting that the JAK pathway deregulation is capable of initiating JMML, and opening new therapeutic options.
Whole exome sequencing undertaken in two siblings with delayed psychomotor development, absent speech, severe intellectual disability and postnatal microcephaly, with brain malformations consisting ...of cerebellar atrophy in the eldest affected and hypoplastic corpus callosum in the younger sister; revealed a homozygous intragenic deletion in VPS51, which encodes the vacuolar protein sorting-associated protein, one the four subunits of the Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes that promotes the fusion of endosome-derived vesicles with the trans-Golgi network (GARP) and recycling endosomes (EARP). This observation supports a pathogenic effect of VPS51 variants, which has only been reported previously once, in a single child with microcephaly. It confirms the key role of membrane trafficking in normal brain development and homeostasis.
Abstract Array-CGH has revealed a large number of copy number variations (CNVs) in patients with multiple congenital anomalies and/or mental retardation (MCA/MR). According to criteria recently ...listed, pathogenicity was clearly suspected for some CNVs but benign CNVs, considered as polymorphisms, have complicated the interpretation of the results. In this study, genomic DNAs from 132 French patients with unexplained mental retardation were analysed by genome wide high-resolution Agilent® 44K oligonucleotide arrays. The results were in accordance with those observed in previous studies: the detection rate of pathogenic CNVs was 14.4%. A non-random involvement of several chromosomal regions was observed. Some of the microimbalances recurrently involved regions (1q21.1, 2q23.1, 2q32q33, 7p13, 17p13.3, 17p11.2, 17q21.31) corresponding to known or novel syndromes. For all the pathogenic CNVs, further cases are needed to allow more accurate genotype–phenotype correlations underscoring the importance of databases to group patients with similar molecular data.
Introduction: Microcephaly is a recurrent feature in patients with inherited bone marrow failure (iBMF) and DNA damage response (DDR) disorders suggesting that common cellular pathways regulate the ...proliferation and differentiation of neural and hematopoietic progenitors. However, while several studies addressed the role of iBFM or DDR genes in brain development, a possible role for microcephaly genes in hematopoietic development has not been investigated. To address this issue, we studied a mouse model of primary microcephaly with biallelic loss-of-function in Mcph1. MCPH1 mutations are found in 10% of patients with isolated forms of genetic microcephaly (MCPH). Interestingly, MCPH1 helps to maintain genomic integrity during cell division by interacting with proteins involved in cell cycle progression, apoptosis or DNA repair, all cellular processes being also involved in iBMF and DDR syndromes.
Methods: Mcph1 null mice were generated by germline deletion of Mcph1 exon 2 (Mcph1tm1.2Kali) (Liang et al., PLoS Genet., 2010). The subpopulations of erythroid progenitors S0 to S5 were phenotypically defined and sorted by flow cytometry according to CD71 and Ter119 expression in the Lin- compartment from mouse liver obtained at birth and during fetal development (E12.5). RNA sequencing (RNA-Seq) was performed on sorted erythroid progenitor fractions obtained from E12.5 fetal livers (SMARTer® Stranded Total RNA-Seq Kit V2-Pico Input library preparation kit). Cell division was studied by multiplexing erythroid specific antibodies with EdU flow cytometry cell proliferation assay.
Results: Null mice recapitulated the microcephaly phenotype seen in MCPH patients, but also showed a striking anemic pallor. Numeration and cytomorphologic examination of peripheral blood at birth confirmed macrocytic anemia with low red blood cell count and anisopoikilocytosis. These observations were consistent with congenital dyserythropoiesis in Mcph1-/- mice and prompted us to further characterize the erythroid lineage.
Quantification of erythroid progenitor populations in liver at birth showed a significant decreased from the S3 subset (Lin-, CD71High, Ter119High) suggesting impaired terminal differentiation. Similar results were obtained in fetal livers at E12.5 indicating that the defect arose early in hematopoietic ontogeny.
Transcriptome analysis of wild-type progenitor populations (S0 to S3) confirmed that Mcph1 is expressed during normal erythropoiesis following a Gata1-like expression profile. This is consistent with the presence in the Mcph1 gene promoter of a binding site for Gata1 and Ldb1 (ENCODE project), supporting an activation by the main erythroid differentiation complex. Strikingly, RNA-Seq analysis revealed deregulation of p53 pathway associated genes in all subsets of Mcph1-/- erythroid progenitors as compared to their wild-type counterparts. Two transcriptional p53 targets involved in cell cycle control, Cdkn1a coding the cyclin-dependent kinase inhibitor (p21) and Ccng1 coding Cyclin G1, were among the most upregulated genes.
Cell cycle analysis performed on sorted erythroid progenitors revealed an endoreduplication phenomenon restricted to the S3 subset with subsequent accumulation of tetraploid cells. Interestingly, physiological endoreduplication is initiated by p21 and E2Fs transcription factors, and Mcph1 functionally interacts with E2f1. Our findings suggest that, in the absence of Mcph1, Cdkn1a overexpression possibly combined to a decreased E2f1 activity may lead to endoreduplication in S3 progenitors, impairing further differentiation into mature red blood cells.
Few data are available for patients with MCPH1 mutations, hematological defects being possibly outlooked due to the severity of the neurological phenotype. However, CBC performed in one of our patients revealed a macrocytosis consistent with dyserythropoiesis evidenced in mice.
Conclusion: We demonstrate for the first time that Mcph1 expression is critical during terminal erythroid differentiation in mice. Altogether our findings provide additional evidence of a unique link between hematopoiesis and neuronal development.
No relevant conflicts of interest to declare.
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