Background Primary microcephaly (MCPH) is a congenital neurodevelopmental disorder manifesting as small brain and intellectual disability. It underlies isolated reduction of the cerebral cortex that is reminiscent of early hominids which makes it suitable model disease to study the hominin‐specific volumetric expansion of brain. Mutations in 25 genes have been reported to cause this disorder. Although majority of these genes were discovered in the Pakistani population, still a significant proportion of these families remains uninvestigated. Methods We studied a cohort of 32 MCPH families from different regions of Pakistan. For disease gene identification, genome‐wide linkage analysis, Sanger sequencing, gene panel, and whole‐exome sequencing were performed. Results By employing these techniques individually or in combination, we were able to discern relevant disease‐causing DNA variants. Collectively, 15 novel mutations were observed in five different MCPH genes; ASPM (10), WDR62 (1), CDK5RAP2 (1), STIL (2), and CEP135 (1). In addition, 16 known mutations were also verified. We reviewed the literature and documented the published mutations in six MCPH genes. Intriguingly, our cohort also revealed a recurrent mutation, c.7782_7783delGA;p.(Lys2595Serfs*6), of ASPM reported worldwide. Drawing from this collective data, we propose two founder mutations, ASPM:c.9557C>G;p.(Ser3186*) and CENPJ:c.18delC;p.(Ser7Profs*2), in the Pakistani population. Conclusions We discovered novel DNA variants, impairing the function of genes indispensable to build a proper functioning brain. Our study expands the mutational spectra of known MCPH genes and also provides supporting evidence to the pathogenicity of previously reported mutations. These novel DNA variants will be helpful for the clinicians and geneticists for establishing reliable diagnostic strategies for MCPH families.

Neurodegenerative and neuropsychiatric diseases are characterized by the structural and functional abnormalities of neurons in certain regions of the brain. These abnormalities, which can result in progressive neuronal degeneration and functional disability, are incurable to date. Although comprehensive efforts have been made to figure out effective therapies against these diseases, partial success has been achieved and complete functional recovery is still not a reality. At present, plants and plant-derived compounds are getting more attention because of a plethora of pharmacological properties, and they are proving to be a better and safer target as therapeutic interventions. This review aims to highlight the roles of tannins, ‘the polyphenol phytochemicals’, in tackling neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases as well as neuropsychiatric disorders like depression. Among the multifarious pharmacological properties of tannins, anti-oxidative, anti-inflammatory, and anti-cholinesterase activities are emphasized more in terms of neuroprotection. The current review also throws light on mechanistic pathways by which various classes of tannins execute neuroprotective effects. Despite their beneficial properties, some harmful effects of tannins have also been elaborated.

Purpose We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. Methods We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable. Results In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability we identified biallelic disease-causing variants in Protocadherin-gamma-C4 (PCDHGC4). Five variants were predicted to induce premature protein truncation leading to a loss of PCDHGC4 function. The three detected missense variants were located in extracellular cadherin (EC) domains EC5 and EC6 of PCDHGC4, and in silico analysis of the affected residues showed that two of these substitutions were predicted to influence the Ca2+-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4. Conclusion We show that biallelic variants in PCDHGC4 are causing a novel autosomal recessive neurodevelopmental disorder and link PCDHGC4 as a member of the clustered PCDH family to a Mendelian disorder in humans.