14q13.1‐21.1 deletion encompassing the HPE8 locus in an adolescent with intellectual disability and bilateral microphthalmia, but without holoprosencephaly

Piccione, Maria; Serra, Gregorio; Consiglio, V; Fiore, Antonella; Cavani, Simona; Grasso, Marina; Malacarne, Michela; Pierluigi, Mauro; Viaggi, Chiara; Corsello, Giovanni

doi:10.1002/ajmg.a.35334

Cited by 18 publications

(15 citation statements)

References 18 publications

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“…Since its discovery as a potential “schizophrenia gene”, NPAS3 has been robustly associated with neurodevelopmental and neuropsychiatric disorders commonly characterized by alterations in white matter connectivity, and intellectual disability. Large scale deletions including NPAS3 have been associated with holoprosencephaly, holoprosencephaly microform and other gross neurodevelopmental abnormalities [ 4 – 6 ]. Smaller deletions physically limited to NPAS3 have been reported as associated with intellectual impairment and disorders of psychosis [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis of NPAS3 functional domains and variants

Luoma

Berry

2018

BMC Molecular Biol

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BackgroundNPAS3 encodes a transcription factor which has been associated with multiple human psychiatric and neurodevelopmental disorders. In mice, deletion of Npas3 was found to cause alterations in neurodevelopment, as well as a marked reduction in neurogenesis in the adult mouse hippocampus. This neurogenic deficit, alongside the reduction in cortical interneuron number, likely contributes to the behavioral and cognitive alterations observed in Npas3 knockout mice. Although loss of Npas3 has been found to affect proliferation and apoptosis, the molecular function of NPAS3 is largely uncharacterized outside of predictions based on its high homology to bHLH–PAS transcription factors. Here we set out to characterize NPAS3 as a transcription factor, and to confirm whether NPAS3 acts as predicted for a Class 1 bHLH–PAS family member.ResultsThrough these studies we have experimentally demonstrated that NPAS3 behaves as a true transcription factor, capable of gene regulation through direct association with DNA. NPAS3 and ARNT are confirmed to directly interact in human cells through both bHLH and PAS dimerization domains. The C-terminus of NPAS3 was found to contain a functional transactivation domain. Further, the NPAS3::ARNT heterodimer was shown to directly regulate the expression of VGF and TXNIP through binding of their proximal promoters. Finally, we assessed the effects of three human variants of NPAS3 on gene regulatory function and do not observe significant deficits.ConclusionsNPAS3 is a true transcription factor capable of regulating expression of target genes through their promoters by directly cooperating with ARNT. The tested human variants of NPAS3 require further characterization to identify their effects on NPAS3 expression and function in the individuals that carry them. These data enhance our understanding of the molecular function of NPAS3 and the mechanism by which it contributes to normal and abnormal neurodevelopment and neural function.Electronic supplementary materialThe online version of this article (10.1186/s12867-018-0117-4) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Molecular analysis of NPAS3 functional domains and variants

Luoma

Berry

2018

BMC Molecular Biol

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“…NPAS3 (14q13.1) encodes a transcription factor localized to the nucleus and may regulate genes involved in neurogenesis. Npas3 −/− mice had abnormal neurodevelopment, neurosignaling and behavior [22], making it a candidate gene of holoprosencephaly (HPE) and hypoplasia of the corpus callosum (ACC) in 14q11-q22 deletion syndrome patients [5, 23]. RALGAPA1 (14q13.2) encodes a major subunit of the RAL-GTPase activating protein, and was suggested to be important in brain development [24].…”

Section: Discussionmentioning

confidence: 99%

A novel 14q13.1–21.1 deletion identified by CNV-Seq in a patient with brain-lung-thyroid syndrome, tooth agenesis and immunodeficiency

Guo

et al. 2019

Mol Cytogenet

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BackgroundChromosome 14q11-q22 deletion syndrome (OMIM 613457) is a rare genomic disorder. The phenotype heterogeneity depends on the deletion size, breakpoints and genes deleted. Critical genes like FOXG1, NKX2–1, PAX9 were identified.Case presentationWe performed whole exome sequencing (WES) and copy number variation sequencing (CNV-seq) for a patient with mild speech and motor developmental delay, short stature, recurrent pulmonary infections, tooth agenesis and triad of brain-lung-thyroid syndrome. By using CNV-seq, we identified a 3.1 Mb de novo interstitial deletion of the 14q13.2q21.1 region encompassing 17 OMIM genes including NKX2–1, PAX9 and NFKBIA. Our patient’s phenotype is consistent with other published 14q13 deletion patients.ConclusionOur results showed the combination of WES and CNV-seq is an effective diagnostic strategy for patients with genetic or genomic disorders. After reviewing published patients, we also proposed a new critical region for 14q13 deletion syndrome with is a more benign disorder compared to 14q11-q22 deletion syndrome.

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“…25,26 Ophthalmological anomalies including coloboma and microphthalmia are frequently present in patients with HPE 27 and heterozygous variants in HPE loci SHH and HPE8 have also been reported in individuals with coloboma without HPE. [28][29][30] CDON is the first HPE gene identified to cause coloboma with a recessive inheritance pattern, in contrast to the dominant pattern observed in HPE. In addition to the previously reported homozygous nonsense allele of uncertain significance, we identified the first com- reported.…”

Section: Methodsmentioning

confidence: 99%

Compound heterozygous splicing CDON variants result in isolated ocular coloboma

et al. 2020

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Ocular coloboma is caused by failure of optic fissure closure during development and recognized as part of the microphthalmia, anophthalmia, and coloboma (MAC) spectrum. While many genes are known to cause colobomatous microphthalmia, relatively few have been reported in coloboma with normal eye size. Genetic analysis including trio exome sequencing and Sanger sequencing was undertaken in a family with two siblings affected with bilateral coloboma of the iris, retina, and choroid. Pathogenic variants in MAC genes were excluded. Trio analysis identified compound heterozygous donor splice site variants in CDON, a cell-surface receptor known to function in the Sonic Hedgehog pathway, c.928 + 1G > A and c.2650 + 1G > T, in both affected individuals. Heterozygous missense and truncating CDON variants are associated with dominant holoprosencephaly (HPE) with incomplete penetrance and Cdon−/− mice display variable HPE and coloboma. A homozygous nonsense allele of uncertain significance was recently identified in a consanguineous patient with coloboma and a second molecular diagnosis. We report the first compound heterozygous variants in CDON as a cause of isolated coloboma. CDON is the first HPE gene identified to cause recessive coloboma. Given the phenotypic overlap, further examination of HPE genes in coloboma is indicated.

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14q13.1‐21.1 deletion encompassing the HPE8 locus in an adolescent with intellectual disability and bilateral microphthalmia, but without holoprosencephaly

Cited by 18 publications

References 18 publications

Molecular analysis of NPAS3 functional domains and variants

Molecular analysis of NPAS3 functional domains and variants

A novel 14q13.1–21.1 deletion identified by CNV-Seq in a patient with brain-lung-thyroid syndrome, tooth agenesis and immunodeficiency

Compound heterozygous splicing CDON variants result in isolated ocular coloboma

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