Simpson‐Golabi‐Behmel syndrome (SGBS) is an X‐linked multiple congenital anomalies and overgrowth syndrome caused by a defect in the glypican‐3 gene (GPC3). Until now, GPC3 mutations have been ...reported in isolated cases or small series and the global genotypic spectrum of these mutations has never been delineated. In this study, we review the 57 previously described GPC3 mutations and significantly expand this mutational spectrum with the description of 29 novel mutations. Compiling our data and those of the literature, we provide an overview of 86 distinct GPC3 mutations identified in 120 unrelated families, ranging from single nucleotide variations to complex genomic rearrangements and dispersed throughout the entire coding region of GPC3. The vast majority of them are deletions or truncating mutations (frameshift, nonsense mutations) predicted to result in a loss‐of‐function. Missense mutations are rare and the two which were functionally characterized, impaired GPC3 function by preventing GPC3 cleavage and cell surface addressing respectively. This report by describing for the first time the wide mutational spectrum of GPC3 could help clinicians and geneticists in interpreting GPC3 variants identified incidentally by high‐throughput sequencing technologies and also reinforces the need for functional validation of non‐truncating mutations (missense, in frame mutations, duplications).
We provide, for the first time, an overview of the mutational spectrum of GPC3, the gene involved in Simpson‐Golabi‐Behmel syndrome, an X‐linked multiple congenital anomalies and overgrowth syndrome, through the description of the 86 distinct mutations, ranging from single nucleotide variations to complex genomic rearrangements, identified until now. The vast majority of these mutations are deletions or truncating mutations (frameshift, nonsense mutations) predicted to result in a loss of function, whereas missense mutations are rare and need functional validation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The X‐linked PTCHD1 gene, encoding a synaptic membrane protein, has been involved in neurodevelopmental disorders with the description of deleterious genomic microdeletions or truncating coding ...mutations. Missense variants were also identified, however, without any functional evidence supporting their pathogenicity level. We investigated 13 missense variants of PTCHD1, including eight previously described (c.152G>A,p.(Ser51Asn); c.217C>T,p.(Leu73Phe); c.517A>G,p.(Ile173Val); c.542A>C,p.(Lys181Thr); c.583G>A,p.(Val195Ile); c.1076A>G,p.(His359Arg); c.1409C>A,p.(Ala470Asp); c.1436A>G,p.(Glu479Gly)), and five novel ones (c.95C>T,p.(Pro32Leu); c.95C>G,p.(Pro32Arg); c.638A>G,p.(Tyr213Cys); c.898G>C,p.(Gly300Arg); c.928G>C,p.(Ala310Pro)) identified in male patients with intellectual disability (ID) and/or autism spectrum disorder (ASD). Interestingly, several of these variants involve amino acids localized in structural domains such as transmembrane segments. To evaluate their potentially deleterious impact on PTCHD1 protein function, we performed in vitro overexpression experiments of the wild‐type and mutated forms of PTCHD1‐GFP in HEK 293T and in Neuro‐2a cell lines as well as in mouse hippocampal primary neuronal cultures. We found that six variants impaired the expression level of the PTCHD1 protein, and were retained in the endoplasmic reticulum suggesting abnormal protein folding. Our functional analyses thus provided evidence of the pathogenic impact of missense variants in PTCHD1, which reinforces the involvement of the PTCHD1 gene in ID and in ASD.
Thirteen missense variants in the PTCHD1 gene associated with X‐linked neurodevelopmental disorder were investigated to address their potentially deleterious impact. Their overexpression in various cell lines (HEK293T, Neuro‐2a) and in primary neuronal cultures revealed abnormal protein stability and impaired subcellular localization, thus providing further evidence for the significant impact of PTCHD1 genetic alterations in intellectual disability and in autism spectrum disorder.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Serine biosynthesis disorders comprise a spectrum of very rare autosomal recessive inborn errors of metabolism with wide phenotypic variability. Neu–Laxova syndrome represents the most severe ...expression and is characterized by multiple congenital anomalies and pre‐ or perinatal lethality. Here, we present the mutation spectrum and a detailed phenotypic analysis in 15 unrelated families with severe types of serine biosynthesis disorders. We identified likely disease‐causing variants in the PHGDH and PSAT1 genes, several of which have not been reported previously. Phenotype analysis and a comprehensive review of the literature corroborates the evidence that serine biosynthesis disorders represent a continuum with varying degrees of phenotypic expression and suggest that even gradual differences at the severe end of the spectrum may be correlated with particular genotypes. We postulate that the individual residual enzyme activity of mutant proteins is the major determinant of the phenotypic variability, but further functional studies are needed to explore effects at the enzyme protein level.
Dimeric PSAT1 structure with the bound pyridoxal 5′‐phosphate shown in stick presentation. In one subunit, variants associated with lethal and nonlethal phenotypes are highlighted by red and orange balls, respectively
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We read with great interest the recent article published by Yooet al1reporting 4 additional Rett-like (RTT) patients with therecurring A567TGABBR2mutation.2More interestingly, theyshowed, with in ...vitro and in vivo functional studies, that theseverity of the phenotype caused byGABBR2mutations wasdirectly linked to their impact onc-aminobutyric acid (GABA)signaling activity, this latter being more reduced with the 2 mis-sense mutations, S695I and I705N, associated with epilepticencephalopathy (EE).1,3They hypothesized that the position ofvariants in different transmembrane (TM) domains ofGABBR2,TM6 for S695I and I705N, and TM3 for A567T, could deter-mine the phenotypic expression. This hypothesis was recentlyreinforced with the report of a novelGABBR2mutation also inTM6 and associated with infantile epileptic spasms.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
CUGC for Simpson-Golabi-Behmel syndrome (SGBS) Vuillaume, Marie-Laure; Moizard, Marie-Pierre; Baumer, Alessandra ...
European journal of human genetics,
04/2019, Volume:
27, Issue:
4
Journal Article
Peer reviewed
Open access
Simpson-Golabi-Behmel syndrome (SGBS). OMIM# OF THE DISEASE: 312870.
GPC3. OMIM# OF THE GENE(S): 300037. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based ...testing for mutations in the GPC3 gene(s) in ⊠ diagnostic, ☐ predictive and ⊠ prenatal settings and for ⊠ risk assessment in relatives.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The 22q11.2 deletion syndrome (22q11DS) is associated with a wide spectrum of cognitive and psychiatric symptoms. Despite the considerable work performed over the past 20 years, the genetic etiology ...of the neurodevelopmental phenotype remains speculative. Here, we report de novo heterozygous truncating variants in the
HIRA
(Histone cell cycle regulation defective, S. Cerevisiae, homolog of, A) gene associated with a neurodevelopmental disorder in two unrelated patients.
HIRA
is located within the commonly deleted region of the 22q11DS and encodes a histone chaperone that regulates neural progenitor proliferation and neurogenesis, and that belongs to the WD40 Repeat (WDR) protein family involved in brain development and neuronal connectivity. To address the specific impact of
HIRA
haploinsufficiency in the neurodevelopmental phenotype of 22q11DS, we combined
Hira
knock-down strategies in developing mouse primary hippocampal neurons, and the direct study of brains from heterozygous
Hira
+/−
mice. Our in vitro analyses revealed that
Hira
gene is mostly expressed during neuritogenesis and early dendritogenesis stages in mouse total brain and in developing primary hippocampal neurons. Moreover, shRNA knock-down experiments showed that a twofold decrease of endogenous
Hira
expression level resulted in an impaired dendritic growth and branching in primary developing hippocampal neuronal cultures. In parallel, in vivo analyses demonstrated that
Hira
+/−
mice displayed subtle neuroanatomical defects including a reduced size of the hippocampus, the fornix and the corpus callosum. Our results suggest that
HIRA
haploinsufficiency would likely contribute to the complex pathophysiology of the neurodevelopmental phenotype of 22q11DS by impairing key processes in neurogenesis and by causing neuroanatomical defects during cerebral development.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The HoxD cluster is critical for vertebrate limb development. Enhancers located in both the telomeric and centromeric gene deserts flanking the cluster regulate the transcription of HoxD genes. In ...rare patients, duplications, balanced translocations or inversions misregulating HOXD genes are responsible for mesomelic dysplasia of the upper and lower limbs. By aCGH, whole-genome mate-pair sequencing, long-range PCR and fiber fluorescent in situ hybridization, we studied patients from two families displaying mesomelic dysplasia limited to the upper limbs. We identified microduplications including the HOXD cluster and showed that microduplications were in an inverted orientation and inserted between the HOXD cluster and the telomeric enhancers. Our results highlight the existence of an autosomal dominant condition consisting of isolated ulnar dysplasia caused by microduplications inserted between the HOXD cluster and the telomeric enhancers. The duplications likely disconnect the HOXD9 to HOXD11 genes from their regulatory sequences. This presumptive loss-of-function may have contributed to the phenotype. In both cases, however, these rearrangements brought HOXD13 closer to telomeric enhancers, suggesting that the alterations derive from the dominant-negative effect of this digit-specific protein when ectopically expressed during the early development of forearms, through the disruption of topologically associating domain structure at the HOXD locus.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
There is a strong evidence for genetic factors as the main causes of Autism Spectrum Disorders (ASD). To date, hundreds of genes have been identified either by copy number variations ...(CNVs) and/or single nucleotide variations. However, despite all the findings, the genetics of these disorders have not been totally explored.
Methods
Thus, the aim of our work was to identify rare CNVs and genes present in these regions in ASD children, using a high‐resolution comparative genomic hybridization technique and quantitative PCR (qPCR) approach.
Results
Our results have shown 60–70 chromosomal aberrations per patient. We have initially selected 66 CNVs that have been further assessed using qPCR. Finally, we have validated 22 CNVs including 11 deletions and 11 duplications. Ten CNVs are de novo, 11 are inherited and one of unknown origin of transmission. Among the CNVs detected, novel ASD candidate genes PJA2, SYNPO, APCS, and TAC1 have been identified in our group of Lebanese patients. In addition, previously described CNVs have been identified containing genes such as SHANK3, MBP, CHL1, and others.
Conclusion
Our study broadens the population spectrum of studied ASD patients and adds new candidates at the list of genes contributing to these disorders.
The aim of our work was to identify rare CNVs and genes present in these regions in Lebanese ASD children, using a high‐resolution comparative genomic hybridization (CGH) technique and quantitative PCR (qPCR) approach. Among the CNVs detected, novel ASD candidate genes PJA2, SYNPO, APCS, and TAC1 have been identified in our group of patients. Our study broadens the population spectrum of studied ASD patients and adds new candidates to the list of genes contributing to these disorders.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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