Phenotypes and genotypes in non‐consanguineous and consanguineous primary microcephaly: High incidence of epilepsy

Duerinckx, Sarah; Désir, Julie; Perazzolo, Camille; Badoer, Cindy; Jacquemin, Valérie; Soblet, Julie; Maystadt, Isabelle; Tunca, Yusuf; Blaumeiser, Bettina; Ceulemans, Berten; Courtens, Winnie; Debray, François-Guillaume; Destrée, Anne; Devriendt, Koenraad; Jansen, Anna; Keymolen, Kathelijn; Lederer, Damien; Loeys, Bart; Meuwissen, Marije; Moortgat, Stéphanie; Mortier, Geert; Nassogne, Marie‐Cécile; Sekhara, Tayeb; Coster, Rudy Van; Ende, Jenny Van Den; Aa, Nathalie Van der; Esch, Hilde Van; Vanakker, Olivier; Verhelst, Hélène; Vilain, Catheline; Weckhuysen, Sarah; Passemard, Sandrine; Verloès, Alain; Aeby, Alec; Deconinck, Nicolas; Bogaert, Patrick Van; Pirson, Isabelle; Abramowicz, Marc

doi:10.1002/mgg3.1768

Cited by 8 publications

(5 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DNAH2 is part of the axonemal inner dynein arm complex and plays a central role in ciliary beating [ 61 ]. Notably, compound heterozygote variants (NM_020877.2: c.2190C > T, p.(Arg244Trp) / c.7192G > C, p.(Gly1911Ala); c.3246C > T, p.(Arg596X) / c.4696A > G, p.(Asp1079Gly)) were found in two different probands presenting primary microcephaly [ 62 ].…”

Section: Resultsmentioning

confidence: 99%

Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance

et al. 2023

View full text Add to dashboard Cite

Background Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH. Materials and methods We sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test. Results In 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls. Conclusion Our study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.

show abstract

Section: Resultsmentioning

confidence: 99%

Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance

et al. 2023

View full text Add to dashboard Cite

show abstract

“…A previous case report documented the co-occurrence of hydrocephalus and developmental disorders in a three-generation Jordanian family with autosomal recessive PCD [21]. Additionally, mutations in the genes Dnah2 and Dnah14, which contribute to motile cilia structure, have been associated with primary microcephaly and neurodevelopmental disorders, along with other conditions such as seizures [22,23]. Dnah2 and Dnah14 are essential for the inner dynein arm structure within the peripheral doublet microtubules of motile cilia [24].…”

Section: Genes Associated With Cilia Motilitymentioning

confidence: 99%

Loss of Dynein Axonemal Heavy Chain 5 Causes Cortical Development Disorders and CSF Flow Stagnation

Sakamoto,

Miyajima,

Nakajima

et al. 2024

Preprint

View full text Add to dashboard Cite

Background: Dynein axonemal heavy chain 5 (Dnah5) has been identified as a key gene associated with primary ciliary dyskinesia in humans. Studies have demonstrated that mice lacking Dnah5 (Dnah5-/-) develop acute hydrocephalus shortly after birth due to impaired ciliary motility, resulting in cerebrospinal fluid (CSF) stagnation and ultimately death within approximately a month. Notably, such hydrocephalus has not been reported in humansharboring this mutation. We aimed to elucidate the pathogenesis of hydrocephalus in Dnah5-deficient mice and by that improve our understanding of the role these pathogenetic mechanisms play in human hydrocephalus. Methods: Using CRISPR/Cas9, we targeted exon 2 of the Dnah5 gene on chromosome 15, introducing a 4-base pair deletion to generate Dnah5-/- mice. We analyzed gene expression in the cerebral cortex using microarrays. Subsequently, we performed immunostaining of the cerebral cortex and ventricular wall using specific antibodies against dynein, n-cadherin, and nestin, and determined the gene expression levels and protein quantities through real-time Polymerase Chain Reaction and Western blot analysis. Results: Hydrocephalus was observed in all Dnah5-/- mice. Electron microscopy images revealed an absence of the axonemal outer dynein arm of the peripheral doublet microtubules. Ventricular size of Dnah5-/- mice was enlarged immediately after birth and it progressed through life. The number of mature neurons in the cerebral motor cortex of Dnah5-/- mice was reduced by approximately 25% compared to wild-type mice. The level ofexpression of the Dynein Cytoplasmic 1 Heavy Chain 1 (Dync1h1) gene was decreased. Cytoplasmic dynein in the cerebral cortex of Dnah5-/- mice showed a 60% decrease compared to the wild-type mice. It was also observed a 32% reduction in nestin and 35% reduction in N-cadherin in the lateral ventricular wall of Dnah5-/- mice. Conclusion: The reduction of cytoplasmic dynein resulted in the suppression of axonal growth and disrupted neurogenesis, and, consequently, a decrease in cell density in the ventricular wall layers. Hydrocephalus in the Dnah5-/- mouse model may arise from the stagnation of CSF due to impaired motile cilia function, and cortical malformations caused by cytoplasmic dynein deficiency.

show abstract

“…The functional neurodevelopmental consequences of PMs include the intellectual disability (ID) of variable severity, behavioral disorders, epilepsy, neurosensory impairments, and cerebral palsy [ 12 , 30 , 49 , 50 , 51 , 52 , 53 ]. Identifying the impact of microcephaly on patients’ intellect is a central issue, as it is necessary to ascertain the degree of autonomy and future social insertion for these individuals.…”

Section: Primary Microcephaly: Small Brain Size or Small Brain And Bo...mentioning

confidence: 99%

“…However, MCDs are rare under this condition, and polymicrogyria (an excessive number of abnormally small cerebral gyri with cortical overfolding) is the only reported MCD in ASPM-PM and has been identified in only four of ninety-seven patients who underwent brain MRI [ 51 , 78 , 79 ]. Epilepsy is much more frequent and affects 20% of patients with ASPM mutations in Europe [ 49 , 51 ]; thus, it is not necessarily caused by an MCD associated with ASPM-PM. A high proportion of this group of patients comes from consanguineous families.…”

Section: Aspm Wdr62 and Dynei...mentioning

confidence: 99%

See 1 more Smart Citation

Genetic Primary Microcephalies: When Centrosome Dysfunction Dictates Brain and Body Size

Farcy,

Hachour,

Bahi-Buisson

et al. 2023

Cells

Self Cite

View full text Add to dashboard Cite

Primary microcephalies (PMs) are defects in brain growth that are detectable at or before birth and are responsible for neurodevelopmental disorders. Most are caused by biallelic or, more rarely, dominant mutations in one of the likely hundreds of genes encoding PM proteins, i.e., ubiquitous centrosome or microtubule-associated proteins required for the division of neural progenitor cells in the embryonic brain. Here, we provide an overview of the different types of PMs, i.e., isolated PMs with or without malformations of cortical development and PMs associated with short stature (microcephalic dwarfism) or sensorineural disorders. We present an overview of the genetic, developmental, neurological, and cognitive aspects characterizing the most representative PMs. The analysis of phenotypic similarities and differences among patients has led scientists to elucidate the roles of these PM proteins in humans. Phenotypic similarities indicate possible redundant functions of a few of these proteins, such as ASPM and WDR62, which play roles only in determining brain size and structure. However, the protein pericentrin (PCNT) is equally required for determining brain and body size. Other PM proteins perform both functions, albeit to different degrees. Finally, by comparing phenotypes, we considered the interrelationships among these proteins.

show abstract

Phenotypes and genotypes in non‐consanguineous and consanguineous primary microcephaly: High incidence of epilepsy

Cited by 8 publications

References 67 publications

Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance

Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance

Loss of Dynein Axonemal Heavy Chain 5 Causes Cortical Development Disorders and CSF Flow Stagnation

Genetic Primary Microcephalies: When Centrosome Dysfunction Dictates Brain and Body Size

Contact Info

Product

Resources

About