Figure - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Compilation of reported cases with microcephaly according to geographic origin, clinical findings, and CENPJ genotypes; SD = standard deviation, NA = not available information, and NR = not reported in the patient.
Source publication
Primary microcephaly (MCPH) is a genetically heterogeneous disorder showing an autosomal recessive mode of inheritance. Patients with MCPH present head circumference values two or three standard deviations (SDs) significantly below the mean for age- and sex-matched populations. MCPH is associated with a nonprogressive mild to severe intellectual di...
Contexts in source publication
Context 1
... the best of our knowledge, this is also the first case of Argentinian origin reported, given that these patients are usually more common in other populations with higher inbreeding rates. To date, all the mutations identified in the CENPJ gene have been reported in a homozygous state, and the vast majority have been reported in consanguineous couples from Pakistan, Brazil, southern Saudi Arabia, and Turkey (Table 2 compiles families and variants reported so far, including our patient). All these reported variants were novel, with the exception of c.18delC (p.Ser7Profs*2), which was reported to be recurrent in Pakistani patients 8 . ...Context 2
... these reported variants were novel, with the exception of c.18delC (p.Ser7Profs*2), which was reported to be recurrent in Pakistani patients 8 . CENPJ pathogenic variants have been described in patients with autosomal recessive primary MCPH type 6 (OMIM 608393) 9,10 , Seckel syndrome type 4 (OMIM 613676) 11 /primordial dwarfism, and in a patient with arthrogryposis and abnormal scar formation, although this last patient had normal growth parameters, including head circumference 6,12 (Table 2). Primary MCPH and primordial dwarfism are considered to belong to a continuous spectrum of phenotypic manifestations, without a clear genotype-phenotype correlation 6 ; this may explain in our patient the head circumference >3 SD below the population mean, with a height lower than expected according to the height of his parents. ...Citations
... A literature review identified 10 consanguineous microcephalic families and one non-microcephalic individual harbouring homozygous CENPJ pathogenic variants, and one microcephalic individual who was compound heterozygous (Table 1) (Bond et al., 2005;Gul et al., 2006;Al-Dosari et al., 2010;Darvish et al., 2010;Sajid Hussain et al., 2013;Bayram et al., 2016;Cueto-González et al., 2020;Khan et al., 2022). Among these cases, we found that epilepsy has been reported only in two consanguineous unrelated families by Darvish et al. (2010) and Khan et al. (2022), although the authors did not detail the seizures nor the EEG pattern. ...
... Despite microcephaly being one of the main characteristics of both the MCPH-SCKL phenotypic spectrum, there is rare evidence of other severe brain malformations in these conditions. Concerning the rare reported cases with pathogenic mutations in CENPJ, only in one recently reported individual (Cueto-González et al., 2020) and in another case included in a cohort study (Oegema et al., 2019), CNS anomalies were described. Brain MRI revealed bilateral migration disorder with heterotopia of the Sylvian fissure, hypoplasia of the corpus callosum, and colpocephaly in the first individual (Cueto-González et al., 2020), nodular heterotopia in peritrigonal regions in the second one (Oegema et al., 2019). ...
Pathogenic variants in CENPJ have been first identified in consanguineous Pakistani families with Hereditary Primary Microcephaly type 6 (MCPH6). In addition to primary microcephaly, the CENPJ-related phenotypic spectrum lately included also distinctive and peculiar ‘bird-like’ craniofacial dysmorphisms, intrauterine and/or postnatal growth retardation, and moderate to severe intellectual disability (ID). These features are also part of the clinical spectrum of Seckel syndrome (SCKL) a genetically heterogeneous neurodevelopmental condition caused by mutations in different genes involved in cell cycle progression. Among these, CENPJ is responsible for type 4 Seckel syndrome (SCKL4). The literature reports two individuals affected by SCKL4 suffering from seizures and other two individuals with other brain malformations in addition to microcephaly. However, neither epilepsy nor brain malformations are described in detail and genotype-phenotype information remains limited. We describe the first Caucasian affected with SCKL4 and harboring a novel, homozygous mutation in CENPJ. We detail the clinical and neuroradiological findings including structural focal epilepsy and a severe brain malformation (i.e., hydranencephaly) that was never associated with SCKL4 to date.
... Patients with MCPH exhibit reduced head circumference and cerebral cortex size, and non-progressive intellectual disability. To date, more than 25 genes have been implicated with MCPH in humans [278]. Following an extensive analysis of databases of genome sequences of consanguineous patients affected by MCPH a single nucleotide mutation was identified in exon 5 of CDK6. ...
Cyclin-dependent kinases (CDKs) are involved in many crucial processes, such as cell cycle and transcription, as well as communication, metabolism, and apoptosis. The kinases are organized in a pathway to ensure that, during cell division, each cell accurately replicates its DNA, and ensure its segregation equally between the two daughter cells. Deregulation of any of the stages of the cell cycle or transcription leads to apoptosis but, if uncorrected, can result in a series of diseases, such as cancer, neurodegenerative diseases (Alzheimer’s or Parkinson’s disease), and stroke. This review presents the current state of knowledge about the characteristics of cyclin-dependent kinases as potential pharmacological targets.
