Impact of different decontamination methods on the reduction of spiromesifen residue in chilli fruits.

Chilli is an indispensable food item in the daily life of humans but it is affected by many insects, so various pesticides, including spiromesifen, are applied to chilli crops to protect this crop from insect infestation. However, the use of pesticides poses environmental and health issues. These issues have raised the demand for pesticide-free chillies among consumers. The primary aim of this study was to assess the efficacy of various decontamination methods in removing spiromesifen residues from chilli fruits. A randomized block design was employed to conduct a supervised field experiment at the Rajasthan Agricultural Research Institute in Durgapura, Jaipur, India. The samples of chillies treated with pesticides are subjected to seven different homemade techniques. The samples were extracted using the QuEChERS method, known for its efficiency, affordability, simplicity, robustness, and safety. The analysis of spiromesifen residues was conducted using gas chromatography (GC) equipped with an electron capture detector (ECD), and the results were verified using gas chromatography-mass spectrometry (GC-MS). Out of several decontamination methods, the lukewarm water treatment was more effective than any other decontamination method, which led to the highest elimination of spiromesifen residue, whereas rinsing with tap water eliminates the least amount of spiromesifen residue. So, the lukewarm water treatment is a safe, cost-effective, and eco-friendly approach to remove spiromesifen residues from Chilli.

Whole exome sequencing identified a homozygous novel variant in DOP1A gene in the Pakistan family with neurodevelopmental disabilities: case report and literature review.

Background: Hereditary neurodevelopmental disorders (NDDs) are prevalent in poorly prognostic pediatric diseases, but the pathogenesis of NDDs is still unclear. Irregular myelination could be one of the possible causes of NDDs. Case presentation: Here, whole exome sequencing was carried out for a consanguineous Pakistani family with NDDs to identify disease-associated variants. The co-segregation of candidate variants in the family was validated using Sanger sequencing. The potential impact of the gene on NDDs has been supported by conservation analysis, protein prediction, and expression analysis. A novel homozygous variant DOP1A(NM_001385863.1):c.2561A>G was identified. It was concluded that the missense variant might affect the protein-protein binding sites of the critical MEC interaction region of DOP1A, and DOP1A-MON2 may cause stability deficits in Golgi-endosome protein traffic. Proteolipid protein (PLP) and myelin-associate glycoprotein (MAG) could be targets of the DOP1A-MON2 Golgi-endosome traffic complex, especially during the fetal stage and the early developmental stages. This further supports the perspective that disorganized myelinogenesis due to congenital DOP1A deficiency might cause neurodevelopmental disorders (NDDs). Conclusion: Our case study revealed the potential pathway of myelinogenesis-relevant NDDs and identified DOP1A as a potential NDDs-relevant gene in humans.

The interleukin-11 receptor variant p.W307R results in craniosynostosis in humans.

Craniosynostosis is characterized by the premature fusion and ossification of one or more of the sutures of the calvaria, often resulting in abnormal features of the face and the skull. In cases in which growth of the brain supersedes available space within the skull, developmental delay or cognitive impairment can occur. A complex interplay of different cell types and multiple signaling pathways are required for correct craniofacial development. In this study, we report on two siblings with craniosynostosis and a homozygous missense pathogenic variant within the IL11RA gene (c.919 T > C; p.W307R). The patients present with craniosynostosis, exophthalmos, delayed tooth eruption, mild platybasia, and a basilar invagination. The p.W307R variant is located within the arginine-tryptophan-zipper within the D3 domain of the IL-11R, a structural element known to be important for the stability of the cytokine receptor. Expression of IL-11R-W307R in cells shows impaired maturation of the IL-11R, no transport to the cell surface and intracellular retention. Accordingly, cells stably expressing IL-11R-W307R do not respond when stimulated with IL-11, arguing for a loss-of-function mutation. In summary, the IL-11R-W307R variant, reported here for the first time to our knowledge, is most likely the causative variant underlying craniosynostosis in these patients.

Genetic Investigation of Consanguineous Pakistani Families Segregating Rare Spinocerebellar Disorders.

Spinocerebellar disorders are a vast group of rare neurogenetic conditions, generally characterized by overlapping clinical symptoms including progressive cerebellar ataxia, spastic paraparesis, cognitive deficiencies, skeletal/muscular and ocular abnormalities. The objective of the present study is to identify the underlying genetic causes of the rare spinocerebellar disorders in the Pakistani population. Herein, nine consanguineous families presenting different spinocerebellar phenotypes have been investigated using whole exome sequencing. Sanger sequencing was performed for segregation analysis in all the available individuals of each family. The molecular analysis of these families identified six novel pathogenic/likely pathogenic variants; ZFYVE26: c.1093del, SACS: c.1201C>T, BICD2: c.2156A>T, ALS2: c.2171-3T>G, ALS2: c.3145T>A, and B4GALNT1: c.334_335dup, and three already reported pathogenic variants; FA2H: c.159_176del, APTX: c.689T>G, and SETX: c.5308_5311del. The clinical features of all patients in each family are concurrent with the already reported cases. Hence, the current study expands the mutation spectrum of rare spinocerebellar disorders and implies the usefulness of next-generation sequencing in combination with clinical investigation for better diagnosis of these overlapping phenotypes.

NGS-driven molecular diagnosis of heterogeneous hereditary neurological disorders reveals novel and known variants in disease-causing genes.

Hereditary neurological disorders (HNDs) are a clinically and genetically heterogeneous group of disorders. These disorders arise from the impaired function of the central or peripheral nervous system due to aberrant electrical impulses. More than 600 various neurological disorders, exhibiting a wide spectrum of overlapping clinical presentations depending on the organ(s) involved, have been documented. Owing to this clinical heterogeneity, diagnosing these disorders has been a challenge for both clinicians and geneticists and a large number of patients are either misdiagnosed or remain entirely undiagnosed. Contribution of genetics to neurological disorders has been recognized since long; however, the complete picture of the underlying molecular bases are under-explored. The aim of this study was to accurately diagnose 11 unrelated Pakistani families with various HNDs deploying NGS as a first step approach. Using exome sequencing and gene panel sequencing, we successfully identified disease-causing genomic variants these families. We report four novel variants, one each in, ECEL1, NALCN, TBR1 and PIGP in four of the pedigrees. In the rest of the seven families, we found five previously reported pathogenic variants in POGZ, FA2H, PLA2G6 and CYP27A1. Of these, three families segregate a homozygous 18 bp in-frame deletion of FA2H, indicating a likely founder mutation segregating in Pakistani population. Genotyping for this mutation can help low-cost population wide screening in the corresponding regions of the country. Our findings not only expand the existing repertoire of mutational spectrum underlying neurological disorders but will also help in genetic testing of individuals with HNDs in other populations.

Perspectives on frailty screening, management and its implementation among acute care providers in Singapore: a qualitative study.

BACKGROUND: COVID-19 pandemic has reminded how older adults with frailty are particularly exposed to adverse outcomes. In the acute care setting, consideration of evidence-based practice related to frailty screening and management is needed to improve the care provided to aging populations. It is important to assess for frailty in acute care so as to establish treatment priorities and goals for the individual. Our study explored understanding on frailty and practice of frailty screening among different acute care professionals in Singapore, and identify barriers and facilitators concerning frailty screening and its implementation. METHODS: A qualitative study using focus group discussion among nurses and individual interviews among physicians from four departments (Accident & Emergency, Anesthesia, General Surgery, Orthopedics) in three acute hospitals from the three public health clusters in Singapore. Participants were recruited through purposive sampling of specific clinicians seeing a high proportion of older patients at the hospitals. Thematic analysis of the data was performed using NVIVO 12.0. RESULTS: Frailty was mainly but inadequately understood as a physical and age-related concept. Screening for frailty in acute care was considered important to identify high risk patients, to implement targeted treatment and care, and to support decision making and prognosis estimation. Specific issues related to screening, management and implementation were identified: cooperation from patient/caregivers, acceptance from healthcare workers/hospital managers, need for dedicated resources, guidelines for follow-up management and consensus on the scope of measurement for different specialties. CONCLUSION: Our findings indicated the need for 1) frailty-related education program for patients/care givers and stakeholders 2) inter-professional collaboration to develop integrated approach for screening and management of hospital patients with frailty and 3) hospital-wide consensus to adopt a common frailty screening tool.

A Homozygous AKNA Frameshift Variant Is Associated with Microcephaly in a Pakistani Family.

Primary microcephaly (MCPH) is a prenatal condition of small brain size with a varying degree of intellectual disability. It is a heterogeneous genetic disorder with 28 associated genes reported so far. Most of these genes encode centrosomal proteins. Recently, AKNA was recognized as a novel centrosomal protein that regulates neurogenesis via microtubule organization, making AKNA a likely candidate gene for MCPH. Using linkage analysis and whole-exome sequencing, we found a frameshift variant in exon 12 of AKNA (NM_030767.4: c.2737delG) that cosegregates with microcephaly, mild intellectual disability and speech impairment in a consanguineous family from Pakistan. This variant is predicted to result in a protein with a truncated C-terminus (p.(Glu913Argfs*42)), which has been shown to be indispensable to AKNA's localization to the centrosome and a normal brain development. Moreover, the amino acid sequence is altered from the beginning of the second of the two PEST domains, which are rich in proline (P), glutamic acid (E), serine (S), and threonine (T) and common to rapidly degraded proteins. An impaired function of the PEST domains may affect the intracellular half-life of the protein. Our genetic findings compellingly substantiate the predicted candidacy, based on its newly ascribed functional features, of the multifaceted protein AKNA for association with MCPH.

A 24-generation-old founder mutation impairs splicing of RBBP8 in Pakistani families affected with Jawad syndrome.

Jawad syndrome is a multiple congenital anomaly and intellectual disability syndrome with mutation in RBBP8 reported only in two families. Here, we report on two new families from Pakistan and identified a previously reported variant in RBBP8, NM_002894.3:c.1808-1809delTA. We could show that this mutation impairs splicing resulting in two different abnormal transcripts. Finally, we could verify a shared haplotype among all four families and estimate the founder event to have occurred some 24 generations ago.

Updates on Clinical and Genetic Heterogeneity of ASPM in 12 Autosomal Recessive Primary Microcephaly Families in Pakistani Population.

Microcephaly (MCPH) is a genetically heterogeneous disorder characterized by non-progressive intellectual disability, small head circumference, and small brain size compared with the age- and sex-matched population. MCPH manifests as an isolated condition or part of another clinical syndrome; so far, 25 genes have been linked with MCPH. Many of these genes are reported in Pakistani population, but due to a high rate of consanguinity, a significant proportion of MCPH cohort is yet to be explored. MCPH5 is the most frequently reported type, accounting for up to 68.75% alone in a genetically constrained population like Pakistan. In the current study, whole exome sequencing (WES) was performed on probands from 10 families sampled from South Waziristan and two families from rural areas of the Pakistani Punjab. Candidate variants were validated through Sanger sequencing in all available family members. Variant filtering and in silico analysis identified three known mutations in ASPM, a MCPH5-associated gene. The founder mutation p.Trp1326* was segregating in 10 families, which further confirmed the evidence that it is the most prominent mutation in Pashtun ethnicity living in Pakistan and Afghanistan. Furthermore, the previously known mutations p.Arg3244* and p.Arg1019* were inherited in two families with Punjab ethnic profile. Collectively, this study added 12 more families to the mutational paradigm of ASPM and expanded the Pakistani MCPH cohort.

Bilaterally Asymmetrical Becker's Nevus.

Becker's nevus is a main epidermal hypermelanotic condition that usually presents in adolescence, though childhood cases are seen less commonly. Congenital cases have been rarely reported. Nevus is usually unilateral having increased pigmentation and is characterized by hypertrichosis. It usually presents as a patch on back, proximal upper extremities, arms and upper trunk. Becker's Nevus presenting as bilateral asymmetrical patch is rare. A case of 23 year's old male with bilateral hyperpigmentad patch over the back has been reported. The histological exams established the clinical hypothesis of Becker's Nevus.

Effectiveness Of Oral Omega 3 In Reducing Mucocutaneous Side Effects Of Oral Isotretinoin In Patients With Acne Vulgaris.

BACKGROUND: Acne vulgaris has been a common clinical condition. Due to. high prevalence and unclear etio-pathogenesis of acne vulgaris, large number of treatment options have been available across the globe. Limited work has been done to explore the options which may manage or prevent these adverse effects and improve the adherence to the prescribed medications. We therefore conducted this trial to look for effectiveness of oral omega 3 in reducing mucocutaneous side effects of oral isotretinoin in patients with acne vulgaris. OBJECTIVE: To look for effectiveness of oral omega 3 in reducing mucocutaneous side effects of oral isotretinoin in patients with acne vulgaris. It was a randomized control trial conducted at Department of Dermatology Pak Emirates Military Hospital Rawalpindi. Ten months, June 2019 to May 2020. METHODS: A total of 60 patients of acne vulgaris put on oral isotretinoin by consultant dermatologist were included in the study. Patients were randomized into groups by lottery method. Group A received the placebo along with oral isotretinoin while Group B received oral omega 3 in standard dose in addition to oral isotretinoin. Comparison was made in both the groups regarding common mucocutaneous side effects. RESULTS: Out of 60patients with acne vulgaris and put on isotretinoin included in the study, 26 (43.3%) received placebo in addition to isotretinoin while 34 (56.7%) received omega 3 in addition to isotretinoin. Forty (66.7%) patients were female while 20 (33.3%) were male. Cheilitis 35 (58.3%) was the commonest side effect followed by lip dryness 33 (55%). Application of chi-square test revealed that cheilitis, lip dryness and xerosis were significantly found in more patients who received placebo as compared to those who received omega 3 along with isotretinoin. CONCLUSION: Mucocutaneous side effects were a very common finding among patients of acne vulgaris managed with isotretinoin. Cheilitis was the most reported mucocutaneous side effects among the target population. This RCT demonstrated that omega 3 was superior to placebo in order to prevent or manage cheilitis, xerosis or dry lips.

Role Of Intralesional Vitamin-D In Viral Wartse.

BACKGROUND: The study was to look for effectiveness of vitamin D-3 in cutaneous warts in comparison with cryotherapy at dermatology department of Pak Emirates Military Hospital Rawalpindi. It was a randomized control trial conducted at the Department of dermatology Pak Emirates Military Hospital Rawalpindi. Ten months, June 2019 to May 2020. METHODS: A total of 50 patients of cutaneous warts diagnosed by consultant dermatologist were included in the study. Patients were randomized into groups by lottery method. Group A received the Intralesional vitamin D 3 while Group B received cryotherapy. Comparison was made in both the groups regarding the response as complete or partial or no resolution of the wart. RESULTS: Out of 50 patients with cutaneous warts on any location of the body, 23 (46%) received intralesional vitamin D3 while 27 (54%) received cryotherapy as allocated treatment. Twenty-four (48%) patients were female while 26 (52%) were male. Planter warts 41 (82%) were the commonest type according to the site of warts followed by palmar 6 (12%). Application of chi-square test revealed that Vitamin D3 was statistically significantly related to complete resolution of warts as compared to cryotherapy (p-value<0.05). CONCLUSION: Cutaneous warts were most commonly seen on the feet of the affected patients. They had a good response to both of the therapies but intralesional vitamin D3 emerged as more effective option of the two in terms of management of these cutaneous warts.

CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model.

Myotonic dystrophy type 1 (DM1) is an RNA-based disease with no current treatment. It is caused by a transcribed CTG repeat expansion within the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Mutant repeat expansion transcripts remain in the nuclei of patients' cells, forming distinct microscopically detectable foci that contribute substantially to the pathophysiology of the condition. Here, we report small-molecule inhibitors that remove nuclear foci and have beneficial effects in the HSALR mouse model, reducing transgene expression, leading to improvements in myotonia, splicing, and centralized nuclei. Using chemoproteomics in combination with cell-based assays, we identify cyclin-dependent kinase 12 (CDK12) as a druggable target for this condition. CDK12 is a protein elevated in DM1 cell lines and patient muscle biopsies, and our results showed that its inhibition led to reduced expression of repeat expansion RNA. Some of the inhibitors identified in this study are currently the subject of clinical trials for other indications and provide valuable starting points for a drug development program in DM1.

Analysis of chemical composition of urinary calculi from Northern border area of Saudi Arabia.

The present study aimed to investigate the chemical composition of urinary calculi in people living in the northern border area of Saudi Arabia and to formulate suggestions for prevention of renal stones. Urinary stones were obtained from patients attending the Urology Departments of Prince Abdul Aziz Bin Musaad Hospital and Central Hospital, Arar, Saudi Arabia. Stones were analyzed using kit for semi-quantitative colorimetric determination of carbonate, calcium, magnesium, ammonium, oxalate, phosphate, uric acid and cysteine; manufactured by LTA s.r.l. Milano 15/F, 20060 Bussero (Milano), Italy. From a total of 55 urinary stones, 49 (89%) were retrieved from males, while 6 (11%) from females. Ages of patients ranged from 15 to 75 years with the mean of 50.22}14.46 and majority of patients were between 31-50 years (69.08%). Most of the patients were overweight (70.91 %) in both the genders. Calcium oxalate stones were 60%, uric acid 18.18% and calcium phosphate 10.90%, while other forms of stones were scarce. It is concluded that upper urinary tract stones were predominant, comprising mostly of calcium oxalate and urate, which could be prevented by control of obesity; moderate intake of meat, dairy products, fruit vegetables (with minimal oxalates); and plenty of fluids.

CDK5RAP2 interaction with components of the Hippo signaling pathway may play a role in primary microcephaly.

Autosomal recessive primary microcephaly (MCPH) is characterized by a substantial reduction in brain size but with normal architecture. It is often linked to mutations in genes coding for centrosomal proteins; however, their role in brain size regulation is not completely understood. By combining homozygosity mapping and whole-exome sequencing in an MCPH family from Pakistan, we identified a novel mutation (XM_011518861.1; c.4114C > T) in CDK5RAP2, the gene associated with primary microcephaly-3 (MCPH3), leading to a premature stop codon (p.Arg1372*). CDK5RAP2 is a component of the pericentriolar material important for the microtubule-organizing function of the centrosome. Patient-derived primary fibroblasts had strongly decreased CDK5RAP2 amounts, showed centrosomal and nuclear abnormalities and exhibited changes in cell size and migration. We further identified an interaction of CDK5RAP2 with the Hippo pathway components MST1 kinase and the transcriptional regulator TAZ. This finding potentially provides a mechanism through which the Hippo pathway with its roles in the regulation of centrosome number is linked to the centrosome. In the patient fibroblasts, we observed higher levels of TAZ and YAP. However, common target genes of the Hippo pathway were downregulated as compared to the control with the exception of BIRC5 (Survivin), which was significantly upregulated. We propose that the centrosomal deficiencies and the altered cellular properties in the patient fibroblasts can also result from the observed changes in the Hippo pathway components which could thus be relevant for MCPH and play a role in brain size regulation and development.

A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency.

BACKGROUND: Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder associated with intellectual disability in one-third of cases. Recent findings support Mendelian inheritance in subgroups of patients with the disease. The purpose of this study was to identify a novel genetic cause of paraplegic CP with intellectual disability in a consanguineous Pakistani family. METHODS: We performed whole-exome sequencing (WES) in two brothers with CP and intellectual disability. Analysis of AP4M1 mRNA was performed using quantitative real-time PCR on total RNA from cultured fibroblasts. The brothers were investigated clinically and by MRI. RESULTS: We identified a novel homozygous AP4M1 mutation c.194_195delAT, p.Y65Ffs*50 in the affected brothers. Quantitative RT-PCR analysis showed markedly reduced AP4M1 mRNA levels suggesting partial non-sense mediated mRNA decay. Several clinical and MRI features were consistent with AP-4 complex deficiency. However, in contrast to previously reported cases with AP4M1 mutations our patients show an aggressive behavior and a relatively late onset of disease. CONCLUSION: This study shows an AP4M1 mutation associated with aggressive behavior in addition to mild dysmorphic features, intellectual disability, spastic paraparesis and reduced head circumference. Our findings expand the clinical spectrum associated with AP-4 complex deficiency and the study illustrates the importance of MRI and WES in the diagnosis of patients with CP and intellectual disability.

Abolished InsP3R2 function inhibits sweat secretion in both humans and mice.

There are 3 major sweat-producing glands present in skin; eccrine, apocrine, and apoeccrine glands. Due to the high rate of secretion, eccrine sweating is a vital regulator of body temperature in response to thermal stress in humans; therefore, an inability to sweat (anhidrosis) results in heat intolerance that may cause impaired consciousness and death. Here, we have reported 5 members of a consanguineous family with generalized, isolated anhidrosis, but morphologically normal eccrine sweat glands. Whole-genome analysis identified the presence of a homozygous missense mutation in ITPR2, which encodes the type 2 inositol 1,4,5-trisphosphate receptor (InsP3R2), that was present in all affected family members. We determined that the mutation is localized within the pore forming region of InsP3R2 and abrogates Ca2+ release from the endoplasmic reticulum, which suggests that intracellular Ca2+ release by InsP3R2 in clear cells of the sweat glands is important for eccrine sweat production. Itpr2-/- mice exhibited a marked reduction in sweat secretion, and evaluation of sweat glands from Itpr2-/- animals revealed a decrease in Ca2+ response compared with controls. Together, our data indicate that loss of InsP3R2-mediated Ca2+ release causes isolated anhidrosis in humans and suggest that specific InsP3R inhibitors have the potential to reduce sweat production in hyperhidrosis.

Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.

Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR) PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC) analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH). Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH.

Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation.

Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of disorders characterized by progressive spasticity and weakness of the lower limbs. Autosomal dominant and 'pure' forms of HSP account for ∼80% of cases in Western societies of whom 10% carry atlastin-1 (ATL1) gene mutations. We report on a large consanguineous family segregating six members with early onset HSP. The pedigree was compatible with both autosomal dominant and autosomal recessive inheritance. Whole-exome sequencing and segregation analysis revealed a homozygous novel missense variant c.353G>A, p.(Arg118Gln) in ATL1 in all six affected family members. Seven heterozygous carriers, five females and two males, showed no clinical signs of HSP with the exception of sub-clinically reduced vibration sensation in one adult female. Our combined findings show that homozygosity for the ATL1 missense variant remains the only plausible cause of HSP, whereas heterozygous carriers are asymptomatic. This apparent autosomal recessive inheritance adds to the clinical complexity of spastic paraplegia 3A and calls for caution using directed genetic screening in HSP.

CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly.

Autosomal recessive primary microcephaly (MCPH) is characterized by reduced head circumference, reduction in the size of the cerebral cortex with otherwise grossly normal brain structure and variable intellectual disability. MCPH is caused by mutations of 11 different genes which code for proteins implicated in cell division and cell cycle regulation. We studied a consanguineous eight-generation family from Pakistan with ten microcephalic children using homozygosity mapping and found a new MCPH locus at HSA 7q21.11-q21.3. Sanger sequencing of the most relevant candidate genes in this region revealed a homozygous single nucleotide substitution c.589G>A in CDK6, which encodes cyclin-dependent kinase 6. The mutation changes a highly conserved alanine at position 197 into threonine (p.Ala197Thr). Post hoc whole-exome sequencing corroborated this mutation's identification as the causal variant. CDK6 is an important protein for the control of the cell cycle and differentiation of various cell types. We show here for the first time that CDK6 associates with the centrosome during mitosis; however, this was not observed in patient fibroblasts. Moreover, the mutant primary fibroblasts exhibited supernumerary centrosomes, disorganized microtubules and mitotic spindles, an increased centrosome nucleus distance, reduced cell proliferation and impaired cell motility and polarity. Upon ectopic expression of the mutant protein and knockdown of CDK6 through shRNA, we noted similar effects. We propose that the identified CDK6 mutation leads to reduced cell proliferation and impairs the correct functioning of the centrosome in microtubule organization and its positioning near the nucleus which are key determinants during neurogenesis.