What next-generation sequencing (NGS) technology has enabled us to learn about primary autosomal recessive microcephaly (MCPH)

Abstract

The impact that next-generation sequencing technology (NGS) is having on many aspects of molecular and cell biology, is becoming increasingly apparent. One of the the most noticeable outcomes of the new technology in human genetics, has been the accelerated rate of identification of disease-causing genes. Especially for rare, heterogeneous disorders, such as autosomal recessive primary microcephaly (MCPH), the handful of genes previously known to harbour disease-causing mutations, has grown at an unprecedented rate within a few years. Knowledge of new genes mutated in MCPH over the last four years has contributed to our understanding of the disorder at both the clinical and cellular levels. The functions of MCPH proteins such as WDR62, CASC5, PHC1, CDK6, CENP-E, CENP-F, CEP63, ZNF335, PLK4 and TUBGPC, have been added to the complex network of critical cellular processes known to be involved in brain growth and size. In addition to the importance of mitotic spindle assembly and structure, centrosome and centriole function and DNA repair and damage response, new mechanisms involving kinetochore-associated proteins and chromatin remodelling complexes have been elucidated. Two of the major contributions to our clinical knowledge are the realisation that primary microcephaly caused by mutations in genes at the MCPH loci is seldom an isolated clinical feature and is often accompanied either by additional cortical malformations or primordial dwarfism. Gene-phenotype correlations are being revisited, with a new dimension of locus heterogeneity and phenotypic variablity being revealed.

Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome

“…Next-generation sequencing studies have identified a number of genes involved in primary autosomal recessive microcephaly [232]. These studies have revealed common targets relating to cell cycle progression and specifically to mitotic spindle formation [233].…”

Novel STIL Compound Heterozygous Mutations Cause Severe Fetal Microcephaly and Centriolar Lengthening

“…tion in mitosis but also in the maintenance of genome stability via the DNA damage repair response pathways [Alcantara and O'Driscoll, 2014;Morris-Rosendahl and Kaindl, 2015]. Morever, in recent years, it has become clear that MCPH has both a genetic and clinical overlap with other neurodevelopmental disorders, such as Seckel syndrome, Meier-Gorlin syndrome, and microcephalic primordial dwarfism.…”

“…Morever, in recent years, it has become clear that MCPH has both a genetic and clinical overlap with other neurodevelopmental disorders, such as Seckel syndrome, Meier-Gorlin syndrome, and microcephalic primordial dwarfism. For instance, biallelic defects in the genes CPAP/CENPJ and CEP152 have been associated to both MCPH and Seckel syndrome [Bond et al, 2005;AlDosari et al, 2010;Guernsey et al, 2010;Kalay et al, 2011], CENPE mutations to MCPH and microcephalic primordial dwarfism [Mirzaa et al, 2014], while STIL mutations have been found both in patients with MCPH and holoprosencephaly (HPE) [Kumar et al, 2009;Kakar et al, 2015;Mouden et al, 2015], leading to the conclusion that this group of disorders may be considered as a clinical continuum rather than individual entities [Barbelanne and Tsang, 2014;Morris-Rosendahl and Kaindl, 2015].…”

Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease

“…Note that while microcephaly can be caused by defects in DSB signaling, the etiology of this disease is varied and can involve defective neural progenitor cell cycle regulation or as a result of more diverse agents such as viral infection (Kaindl, 2014; Mahmood et al, 2011; Manicklal et al, 2013; Morris-Rosendahl and Kaindl, 2015; Noyola et al, 2001; Tang et al, 2016; Woods et al, 2005). For example, hereditary mutations in the NHEJ factors LIG4 and XLF or hypomorphic mutations in Nijmegen breakage syndrome 1 (NBS1) and certain mutations of MRE11, both components of the MRN complex that is essential for HR and DSBR, also results in microcephaly (Frappart and McKinnon, 2006; Matsumoto et al, 2011; O’Driscoll and Jeggo, 2006; Stracker and Petrini, 2011).…”

“…In essence, these syndromes reflect two distinct features of perturbed neural homeostasis. Microcephaly is a congenital birth defect that is the result of abnormal neural development, and as such reflects malformations that occurred prior to birth (Kaindl et al, 2010; Morris-Rosendahl and Kaindl, 2015; Woods et al, 2005). In contrast, the cerebellar atrophy resulting from neurodegeneration, and the ongoing postnatal neural cell death that eventually results in an individual being wheelchair bound, are events that manifest some months or years after birth.…”