Autosomal Recessive Primary Microcephaly (MCPH) is a rare disorder of neurogenic mitosis characterized by reduced head circumference at birth with variable degree of mental retardation. In MCPH patients, brain size reduced to almost one-third of its original volume due to reduced number of generated cerebral cortical neurons during embryonic neurogensis. So far, seven genetic loci (MCPH1-7) for this condition have been mapped with seven corresponding genes (MCPH1,WDR62,CDK5RAP2,CEP152,ASPM,CENPJ, andSTIL) identified from different world populations. Contribution ofASPMandWDR62gene mutations in MCPH World wide is more than 50%. By and large, primary microcephaly patients are phenotypically indistinguishable, however, recent studies in patients with mutations inMCPH1, WDR62andASPMgenes showed a broader clinical and/or cellular phenotype. It has been proposed that mutations in MCPH genes can cause the disease phenotype by disturbing: 1) orientation of mitotic spindles, 2) chromosome condensation mechanism during embryonic neurogenesis, 3) DNA damage-response signaling, 4) transcriptional regulations and microtubule dynamics, 5) certain unknown centrosomal mechanisms that control the number of neurons generated by neural precursor cells. Recent discoveries of mammalian models for MCPH have open up horizons for researchers to add more knowledge regarding the etiology and pathophysiology of MCPH. High incidence of MCPH in Pakistani population reflects the most probable involvement of consanguinity. Genetic counseling and clinical management through carrier detection/prenatal diagnosis in MCPH families can help reducing the incidence of this autosomal recessive disorder.

Autosomal recessive primary microcephaly (MCPH) is a rare human genetic disorder in which the head circumference is reduced because of abnormality in fetal brain growth. To date, six loci and four genes have been identified for this condition. Our study of primary MCPH led to the identification of 33 Pakistani families with different ethnic backgrounds. Most of these families showed linkage to MCPH5 locus on chromosome 1q31. Only one family with Pashtoon origin from a remote region in Pakistan linked to MCPH6 locus on chromosome 13q12.12-q12.13. Sequence analysis of exon 11 of CENPJ gene, located at MCPH6 locus, revealed a novel four base pair deletion mutation, which is predicted to be protein truncating.

Ectodermal-dysplasia-syndactyly syndrome (EDSS1) is a rare form of ectodermal dysplasia (ED), affecting skin and its appendages mainly hair, teeth and nails. In the present study, we have investigated a large consanguineous Pakistani family with 10 individuals showing features of EDSS1. Human genome was screened using highly polymorphic microsatellite markers to identify the gene causing EDSS1. The disease locus for EDSS1 was assigned to chromosome 1q23.1-q23.3. This region corresponds to 5.63 Mb according to the sequenced based physical map (Build 36.2) of the human genome and flanked by markers D1S1653 and D1S1677. A maximum two-point LOD score of 5.05 was obtained with the marker D1S484. Sequence analysis revealed a homozygous missense mutation (c.635C>G; p.Pro212Arg) in the recently reported PVRL4 gene causing EDSS1. The involvement of mutant nectin-4 in causing EDSS1 may open up interesting prospectives into the role of cell adhesion molecules in causing syndromic forms of EDs.

Tooth agenesis constitutes the most common anomaly of dental development in humans. In the majority of familial cases of hypodontia alone or in association with other anomalies, the mode of inheritance is autosomal dominant. In the present study, we have identified two distantly related consanguineous Pakistani kindreds with an autosomal recessive form of oligodontia with associated dental anomalies. Locus in this case has been mapped on chromosome 4p16.1-p16.3. The maximum two-point LOD score of 2.85 (θ=0.0) was obtained at markers D4S2925 and D4S2285. A maximum multipoint LOD score exceeding 4 was obtained at the same markers. Recombination events observed in affected individuals localized the disease locus between markers D4S412 and D4S2935, spanning a 9.24-cM region on chromosome 4p16.1-p16.3. Sequence analysis of candidate gene MSX1 revealed a novel recessive missense mutation resulting in substitution of alanine to threonine amino acid (p. A219T), located in the MSX1 homeodomain, which is important for DNA binding and protein-protein interaction. The mutation, p. A219T, is the first recessive mutation identified in MSX1.