For various reasons, Pakistan is an ideal ground for the study of hereditary and congenital anomalies. These reasons include extended families, large sib-ships and inbred unions. Owing to its historical and geopolitical aspects, the Pakistani population is comprised of a unique combination of a large number of ethnic, linguistic and socio-demographic strata. To the interest of human biologists and geneticists, different ethnic groups exhibit a distinct pattern of hereditary and congenital anomalies likely due to their distinct genetic ancestry, consanguinity and population structure. Hence, hereditary and congenital anomalies are commonly observed in the clinical practice and one is surprised to see odd and anomalous phenotypic presentations. These facts give reasons to study the nature and pathomorphogenesis of the anomalies prevailing in our society. This study was aimed at describing the phenotypic and molecular genetic aspects of various rare, hereditary and congenital anomalies mostly related to limb morphology, among the Pakistani subjects/families. Subjects/families with hereditary and congenital anomalies were recruited through field visits in various towns of Southern Punjab. Most of the subjects were ascertained with the help of local resource persons including para-medical staff, teachers and social workers. Subject/families were also recruited from district hospitals. Clinical data including photographs, radiographs, MRI, and laboratory investigations were obtained accordingly at the nearest tertiary care hospitals. Phenotypic characterization was carried out with the help of resident officers and specialized doctors at the tertiary care hospitals. Descriptive statistics were utilized for the analyses of data from large cohorts of subjects with similar phenotypic presentations. For molecular characterization, PCR based Sanger sequencing, homozygosity mapping through SNP-based linkage analysis, and exome sequencing were carried out. The results obtained throughout the study period are described in the six chapters (first chapter presents a general introduction) of this dissertation. In Chapter 2, the clinical and epidemiological aspects of 103 independent probands with polydactyly are presented. These probands exhibited different types of polydactylies which varied in the combination of involved limb, laterality and symmetry. In 67% of subjects, upper limbs were involved and 33% had lower limb involvement. The polydactylies were characterized as type I, II, and IV (3 preaxial polydactylies), type A and B (2 postaxial polydactylies. This is the largest cohort of polydactyly cases reported from Pakistan. In Chapter 3, a molecular study of a Baloch tribe kindred with polydactyly is presented. A novel ZRS c.287C>A (chr7:156,584,283) mutation was observed that segregate with preaxial polydactyly type II or triphalangeal thumb polydactyly (TPT; OMIM 174500) in an extended Balochi tribe family. The phenotypic features of TPT were triphalangeal thumb with or without thumb polydactyly, bilateral small knob-like outgrowth on the little finger and clino-camptodactylous appearance of the involved digits, making it distinct from the reported typical TPT phenotypes. The inheritance pattern was autosomal dominant. In Chapter 4, the clinical aspects of rare limb reduction defects are presented. The clinical evaluation of four patients who were recruited from various towns of Punjab was carried out. The recruited cases of limb reduction defects had sporadic and isolated phenotypes. In Chapter 5, two unrelated families with Cenani-Lenz syndactyly, which is a rare and one of the most severe syndactyly types, are presented. Here, two mutations were identified by direct PCR based Sanger sequencing (c.316+1G>A and c.1151A>G) and found to segregate with the phenotypes. Both variants were predicted to be pathogenic by bioinformatics analyses. In Chapter 6, a sporadic case of a male patient with brachydactyly type B1 is presented. The clinical symptoms in this patient were the congenital absence of 2nd phalanges with hypoplasia/absence of last terminal phalanx in all fingers/toes except thumb/big toe in all limbs. This phenotype was due to de novo heterozygous mutation c.2265 C > Ap.Y755* in exon 9 of ROR2. In Chapter 7, the case of a large family initially diagnosed with intellectual disability but later proved to be the case of hypothyroidism, is presented. The phenotype was quite diverse and puzzling and segregated in an autosomal recessive manner in the pedigree. SNPbased genotyping of this family lead to the identification of homozygous intervals common among the affected subjects, and a large number of intellectual disability-related genes were excluded. Whole exome sequencing led to the identification of genetic alteration c.719A>G in the TPO gene as a likely cause of autosomal recessive congenital hypothyroidism with intellectual disability in the family. Overall, the study findings improve our understanding of clinical and molecular aspects of polydactyly, limb reduction defects, Cenani-Lenz syndactyly, brachydactyly, and congenital hypothyroidism with intellectual disability. This study will be beneficial for clinicians, researchers, and genetic counselor and government officials for implementing programs of genetic testing, counseling and management for hereditary anomalies.