Incidence Of Autosomal Recessive Disorders Research Articles

Autosomal Recessive Inherited Bleeding Disorders in Pakistan, a Cross Sectional Study from Selected Regions

INTRODUCTION: Incidence of autosomal recessive disorders is rare, includes deficiencies of clotting factors I, II, V, VII, X, XI, XIII, vitamin K dependent clotting factors, combined factor V & VIII, Von Willebrand disease type 3, Glanzmann Thrombasthenia and Bernard Soulier syndrome.OBJECTIVE: Spectrum of autosomal recessive bleeding disorders (ARBDs] among Pakistani patients.PATIENTS AND METHODS: This cross-sectional study was carried out at Karachi, Lahore, Islamabad and Peshawar. PT,aPTT, BT, and fibrinogen levels done. Patients with prolonged APTT were tested for factors VIII and IX. If FVIII was low, von Willebrand factor: antigen (vWF: Ag) and von Willebrand factor: ristocetin cofactor (vWF: RCo) were performed. When PT and aPTT both were prolonged, FII, FV, and FX were tested. Peripheral film and platelet aggregation studies were done for platelet disorders. Urea clot solubility test was done at the end.RESULTS: Out of429 patients, 148 were diagnosed with Hemophilia A, remaining 281 patients had ARBDs. 95 (33.8%) had VWD type 3. Fibrinogen deficiency was found in 34 (12%), Glanzmann Thrombasthenia in 27 (9.6%), factor XIII in 13 (4.6%), factor VII in 12 (4.3%), factor V in 9 (3.2%), 8 (2.8%) in vitamin K dependent clotting factors, , Bernard Soulier in 7 patient (2.5%),factor X in 2 (0.7%), factor II in 2 (0.7%), factor XI and combined factor V and VIII in 1 (0.4%)patients each. 70 patients (16.3%) remained undiagnosed.CONCLUSION: VWD type 3 is the most common deficiency followed by fibrinogen deficiency. Glanzmann thrombasthenia was the third most common ARBD. DisclosuresNo relevant conflicts of interest to declare.

Expanded genetic screening panel for the Ashkenazi Jewish population.

Carrier screening programs that identify the presence of known mutations have been effective for reducing the incidence of autosomal recessive conditions in the Ashkenazi Jewish (AJ) population and other populations. Yet, these programs have not realized their full potential. Furthermore, many known autosomal recessive and dominant conditions are not screened for and the molecular basis of other conditions for which screening might be offered is unknown. Through literature review and annotation of full sequenced genomes from healthy individuals, we expanded the list of mutations. Mutations were identified in a sample of 128 fully sequenced AJ genomes that were filtered through clinical databases and curated manually for clinical validity and utility using the American College of Medical Genetics and Genomics scoring (ACMG) system. Other known mutations were identified through literature review. A panel of 163 mutations was identified for 76 autosomal recessive, 24 autosomal dominant, and 3 X-linked disorders. Screening for a broader range of disorders not only could further reduce the incidence of autosomal recessive disorders but also could offer the benefits of early or presymptomatic diagnosis.Genet Med 18 5, 522-528.

Spinal muscular atrophy: Clinical spectrum and genetic mutations in Pakistani children

In Pakistan the rate of consanguineous marriages is high, thus, the chance of incidence of autosomal recessive disorders is likely to be high. The aim of this study is to investigate the clinical characteristics and genetics of spinal muscular atrophy (SMA) in children who presented to Aga Khan University, Karachi. This study was a retrospective review of the medical charts of children (neonate: 15 years) with discharge diagnosis of SMA during last 10 years. Demographic features, consanguinity, and diagnostic analysis (including genetic analysis) were noted. During the study period 67 children had a discharge diagnosis of SMA. Werdnig Hoffman disease (SMA type I) was the commonest variant seen in 37 (56%) children. Overall 68% were infants. High parental consanguinity was observed in 68% of the study cohort. The history of delayed development and undiagnosed early death was observed in the families of 19 children. Genetic testing was performed in 22 (33%) children. Survival motor neuron (SMN) 1 gene deletion was found in 19 (86%) of the 22 patients in whom the gene analysis was done and 13 (68%) were also positive for neuronal apoptosis inhibitory proteins (NAIP) deletion. SMA is not an uncommon neurodegenerative disorder in Pakistan and SMA type I was the most common type. SMN1 gene deletion was the most common genetic deletion found in this study. In addition, family history of developmental delay and frequent early deaths highlights the need for implementation of prenatal diagnosis for early detection, effective control, and management of this disorder in Pakistan.

Developing and evaluating a culturally appropriate genetic service for consanguineous South Asian families.

Blackburn with Darwen Primary Care Trust (PCT) provides services to a substantial Asian population in which the practice of consanguineous marriage is common and there is a high incidence of autosomal recessive disorders. The aim was to provide and evaluate a genetic service accessible to consanguineous families from the South Asian community who had a child affected by an autosomal recessive disorder. Information on genetic risk was provided along with the offer of genetic testing for members of the extended family to identify gene carriers and facilitate informed reproductive choices. An Urdu-speaking health visitor was employed to establish a community-based, hospital-linked genetic service in conjunction with local paediatric and regional genetic services offered to parents who had an affected child and 71 of their relatives. The service was evaluated using a specifically designed questionnaire. There was a high uptake of the service (95% of index parents and 92% of relatives to whom it was offered) and a high uptake of carrier testing (94% of relatives to whom it was offered). Eight requests for prenatal diagnosis were made during the course of the service development. Many individuals stated they would consider genetic risk when making future marriage and reproductive plans. Input from a health care worker from the same ethnic background who provided information in their own language was highly valued. Family orientated genetic services for ethnic groups practicing consanguinity can be acceptable and effective when provided in a culturally appropriate manner.

Perinatal mortality in different ethnic groups.

We have analysed the cause of perinatal deaths in four hospitals in the North West Thames region over a six year period commencing January 1980. The Pakistani population had a significantly greater perinatal mortality rate (15.7/1000 births) than the Europeans (11.3/1000 births). This was due to an increased incidence of macerated stillbirths and lethal malformations, the latter resulting from a significantly higher incidence of autosomal recessive disorders, neural tube defects, and renal malformations.

Inbreeding and genetic disease in Sottunga, Finland.

The contribution of inbreeding to the prevalence of recessive genetic diseases in the Aland Island parish of Sottunga is investigated. Genealogical data for 3,030 individuals spanning up to 15 generations were used to estimate inbreeding. This small island community shows a low average inbreeding value of .0031 for the period 1725-1975. A cohort analysis shows that inbreeding increased from 1750 to 1900, when maximum inbreeding for those born in Sottunga reached .0057. A sharp decline in inbreeding occurred thereafter. Individuals with island-born parents made the largest contributions to inbreeding in all time periods compared to those with one or two migrant parents. These trends are consistent with changing migration patterns and isolate breakdown in Aland since 1900. An analysis of pedigree development demonstrates that remote consanguinity contributed more to inbreeding through time than close consanguinity. Both the number of common ancestors and the number of paths of relationship between spouses increased dramatically through time, the latter at a much faster rate. The contribution to average inbreeding per path, however, diminished rapidly through time. This analysis indicates that inbreeding does not account for the high incidence of autosomal recessive disorders, such as tapetoretinal disease, found in the parish.

An expected decrease in the incidence of autosomal recessive disease due to decreasing consanguineous marriages.

A recent decline in consanguineous marriages in Japan should have resulted in a decrease in the incidence of autosomal recessive disorders. Theoretical estimates were made of the chronological decrease in the incidence using a formula for Hardy-Weinberg expectation in a partially inbred population and applying appropriate consanguinity rates, taken from the literature, during the period from 1942 to 1983. Theoretically estimated also, using Nei's extended Dahlberg's formula, is a chronological decrease in the proportion of first-cousin marriages among the parents of affected individuals. The estimated decrease in both indices during the period was substantial, and greater in disorders of low gene frequencies. The incidence of major autosomal recessive disorders was estimated to have decreased by 40 to 80% during the period. The proportion of first-cousin marriages among the parents of affected individuals dropped from 40-70% in 1945 to 5-15% in 1983. Theoretical estimates of the magnitude of the decrease in the incidence and in the proportion of first-cousin marriages among the parents agreed fairly well with those of observed figures in phenylketonuria and Wilson's disease.