MCPH1 deletion in a newborn with severe microcephaly and premature chromosome condensation

A newborn with severe microcephaly and a history of parental consanguinity was referred for cytogenetic analysis and subsequently for genetic evaluation. While a 46,XY karyotype was eventually obtained, premature chromosome condensation was observed. A head MRI confirmed primary microcephaly. This combination of features focused clinical interest on the MCPH1 gene and directed genetic testing by sequence analysis and duplication/deletion studies disclosed a homozygous deletion of exons 1–11 of the MCPH1 gene. This case illustrates a strength of standard cytogenetic evaluation in directing molecular testing to a single target gene in this disorder, allowing much more rapid diagnosis at a substantial cost savings for this family.     

Analysis of 21 autosomal STRs in Saudi Arabia reveals population structure and the influence of consanguinity

Variation in the 21 autosomal STRs detected by the GlobalFiler multiplex was investigated in a sample of 523 indigenous male Arabs from five geographic regions of Saudi Arabia. Although allele frequencies for the entire dataset were found to be broadly similar to those determined in previous studies of Saudi citizens, significant differences were found among regions. Heterozygote deficiency was observed at nearly all loci in all regions, probably as a consequence of high levels of consanguineous marriage; in the case of D2S1338, which showed the largest deviation from Hardy-Weinberg equilibrium, the presence of a null allele also played a part. Genetic distances were greatest between the Northern and Southern regions, whilst the West, Central and East appeared most similar to each other, and to previously published surveys. This contrasts with previously described variation among paternal lineages in the same sample-set: Y-chromosome variation was limited within the North/Central/South core compared with the more diverse East and West. Differences between autosomal and Y-chromosomal patterns may reflect genetic drift on the Y chromosome, exacerbated by prevalent patrilineal descent groups in different regions.     

Consanguinity profile in the Gaza Strip of Palestine: Large-scale community-based study

Consanguineous marriages which have been practiced throughout history continue to be practiced within different ethnic, religious and social groups to varying degrees with highest prevalences in North Africa, Middle East and central and south Asia. In the Gaza Strip of Palestine, little is known about the consanguinity profile, so the present large-scale study aims to explore the consanguinity profile of two generations using data from the β-thalassemia premarital screening program. Sociodemographic data analysis included 156,635 (141,200 males and 15,435 females) persons and their parents, representing 141,200 couples who were referred to the Thalassemia and Hemophilia Center for premarital testing. In addition, the consanguinity characteristics of parents of 217 transfusion-dependent β-thalassemic non-sibling patients were analyzed. Results revealed a significant decrease in the overall prevalence of consanguineous (first- and second-cousin) marriages between the previous (fathers') generation (45.2%) and the current (groom/bride) generation (39.9%). Among the five governorates of the Gaza Strip, records of Gaza Governorate revealed the lowest occurrence (36.9% current generation and 42.1% previous generation) of consanguineous marriages, as compared to all others. Consanguineous marriages are significantly higher in semi-urban areas (41.6%) than in urban areas (39.1%) in the current generation (previous generation, 46.4% vs 44.7%, respectively). Compound consanguinity (two generation) and a single level of consanguinity were seen in 20.7% and 43.7%, respectively, of the cases. The average age of those with first-cousin marriages is significantly lower (22.4 ± 4.4 years) than those with second-cousin marriages (24.3 ± 6.1 years) and the non-consanguineous (26.5 ± 8.2 years). The rate of consanguineous marriages among never married people (42.2%) is significantly much higher than the rate of people with multiple marriages (18.1%). About 74.7% of the non-sibling thalassemic patients of the Gaza Strip are associated with consanguineous parents, of them 54.4% first-cousins and 20.3% second-cousins.In conclusion, although there is a decline in the consanguinity profile in the present compared to previous generation, consanguineous marriages are still a common practice in the Gaza Strip, which rationalizes the necessity for more awareness and counseling efforts about the potential health-related risks of consanguinity on individual lives and the population overall.     

A new familial sclerosing bone dysplasia

Osteoscleroses are a heterogeneous group of bone remodeling disorders characterized by an increase in bone density. Here we report on a consanguineous Lebanese family in which two sisters, aged 39 and 36 years, exhibit a severe genu varum, a square‐face appearance, high forehead, slight proptosis of the eyes, symmetric enlargement of the jaw, protruding chin, and short stature. Bone X‐rays showed the presence of hyperostosis of the cranial base and vault with increased density of the orbits, hyperostosis of the bones, thickening of the cortices, diaphyseal modeling defects, cortical thickening of the medullary cavity, mild enlargement of the medullary cavity of the short long bones, short femoral necks, increased width of the ribs, and narrow interpedicular distances of the lower lumbar spine. Osteodensitometry showed values 200% to 300% above values for age. A cervical MRI revealed the presence of a diffuse osteosclerosis with calcification of the posterior vertebral ligament and a narrow canal between C2 and T2. Blood test results were unremarkable. Serum osteocalcin levels were in the normal range, whereas high values of serum C ‐ telopeptide were noted. A bone biopsy showed only the presence of compact bone and did not allow for histomorphometric analysis. Molecular studies excluded genes known to be involved in sclerosing bone dysplasias as the cause of this condition. In vitro analysis of osteoclast function indicated that contrary to most cases of autosomal recessive osteopetrosis, osteoclasts both formed and resorbed but exhibited a small decrease in resorptive activity compared with osteoclasts generated from normal control individuals. Differential diagnoses are discussed, and the possibility that this may be a novel clinical entity is raised. © 2010 American Society for Bone and Mineral Research.     

Clinical characteristics of neonates with inborn errors of metabolism detected by Tandem MS analysis in Oman

We reviewed the clinical profile of our neonates diagnosed to have inborn errors of metabolism (IEM) by Tandem Mass Spectrometry (TMS) over a seven years period, and compared the results with published reports. We also attempted to evaluate various clinical situations wherein the screening test would yield a high pick up rate. Among the 166 neonates studied (10 aged 1 day, 79 aged 2-7 days and 77 aged 8-28 days), significant abnormalities on TMS suggestive of IEM were detected in 38 babies (23%), most common diseases diagnosed were maple syrup urine disease (10 neonates), propionic acidemia (8 neonates), urea cycle diseases (6 neonates) and isovaleric acidemia (4 neonates). The detection incidence was calculated to be one positive case out of every 4 to 5 babies tested. A high prevalence of parental consanguinity and high level of positive family history of affected siblings were the highlights of this study. The major clinical situations where testing was helpful were (a) unexplained acute neonatal encephalopathy, (b) positive family history of known or suspected IEM and (c) new born presenting with abnormal serum biochemistry suggestive of IEM.     

Desmosterolosis presenting with multiple congenital anomalies

Desmosterolosis is a rare multiple congenital anomaly syndrome caused by a defect in the enzyme 3-beta-hydroxysterol delta-24-reductase (DHCR24) in the cholesterol biosynthesis pathway. Defects in this enzyme cause increased level of the cholesterol precursor desmosterol while disrupting development of cholesterol, impacting embryogenesis. A total of 9 cases of desmosterolosis have been reported to date. We report a 20-month-old male from consanguineous parents with multiple congenital anomalies including corpus callosum hypoplasia, facial dysmorphism, cleft palate, pectus deformity, short and wide neck and distal contractures. On analysis of the regions of homozygosity found by microarray, we identified DHCR24 as a candidate gene. Sterol quantitation showed a desmosterol level of 162 μg/mL (nl: 0.82 ± 0.48). Genetic testing confirmed the diagnosis with a homozygous likely pathogenic mutation (p.Glu191Lys) in the DHCR24 gene. Our case expands the known diagnostic spectrum for Desmosterolosis. We suggest considering Desmosterolosis in the differential diagnosis of patients who present with concurrent agenesis of the corpus callosum with white matter atrophy and ventriculomegaly, retromicrognathia with or without cleft palate, hand contractures, and delay of growth and development. Children of consanguineous mattings may be at higher risk for rare recessive disorders and testing for cholesterol synthesis defect should be a consideration for affected children. Initial evaluation can be performed using sterol quantitation, followed by genetic testing.     

Mental retardation in Norway: prevalence and sub-classification in a cohort of 30 037 children born between 1980 and 1985

Objectives: We wanted to determine the prevalence and subcategories of mental retardation (MR) defined as IQ ≤ 70 in Akershus county, which rated by average yearly income, had the second highest socioeconomic status (SES) in Norway. Methods: The study population consisted of 30 037 children born between 1980 and 1985. Cases were ascertained from multiple sources and psychometrically assessed, predominantly with the Wechsler tests, which were standardized in Norway in 1978. The cases were divided into four groups: profound (IQ <20), severe (IQ 20-34), moderate (IQ 35-49), and mild (IQ 50–70) MR, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). The median age was 10.8 y. The frequency and degree of parental consanguinity were registered, and the average inbreeding coefficient was calculated. Results: Altogether, 185 had IQ ≤ 70, giving a prevalence of MR of 6.2/1000. Prevalences for profound, severe, moderate, and mild MR were 0.8, 0.4, 1.5 and 3.5/1000, respectively. In two, possibly three, cases the parents were second cousins, giving an average inbreeding coefficient of 20-30 × 10^-5. Conclusions: The low prevalence of MR, particularly mild MR, could partly be explained by high SES, old standardization of IQ-test, and low inbreeding coefficient. The proportion of profound MR was considerably higher than estimated by DSM-IV.     

Genetic heterogeneity of megaloblastic anaemia type 1 in Tunisian patients

Megaloblastic anaemia 1 (MGA1) is a rare autosomal recessive condition characterized by selective intestinal vitamin B12 malabsorption and proteinuria. More than 200 MGA1 patients have been identified worldwide, but the disease is relatively prevalent in Finland, Norway and several Eastern Mediterranean regions. MGA1 is genetically heterogeneous and can be caused by mutations in either the cubilin (CUBN) or the amnionless (AMN) gene. In the present study we investigated the molecular defect underlying MGA1 in nine Tunisian patients belonging to six unrelated consanguineous families. Haplotype and linkage analyses, using microsatellite markers surrounding both CUBN and AMN genes, indicated that four out of the six families were likely to be linked to the CUBN gene. Patients from these families were screened for the Finnish, Mediterranean and Arabian mutations already published. None of the screened mutations could be detected in our population. One family showed a linkage to AMN gene. Direct screening of the AMN gene allowed the identification of the c.208-2A>G mutation, previously described in a Jewish Israeli patient of Tunisian origin and in Turkish patients. This suggests that the c.208-2A>G mutation may derive from a single Mediterranean founder ancestor. For the last family, haplotype analysis excluded both CUBN and AMN genes, suggesting the existence of a third locus that may cause MGA1.     

Consanguinity among Parents of Hearing-Impaired Children in Relation to Ethnic Groups in the Jewish Population of Jerusalem

A longitudinal study was performed on Jewish children with moderately-severe to profound hearing impairment born in Jerusalem during a period of 15 years (1967-1982), and the data on consanguineous matings among their parents were analyzed. These data were estimated in relation to the records obtained in an earlier survey performed on Jewish deaf children during the years 1955-1964. The rate of consanguinity among the parents of hearing-impaired children was much lower in the present survey than in the earlier one in both the Ashkenazi (Central and Eastern European origin) and the non-Ashkenazi (Asian-African origin) group. It is assumed that there is a better understanding of the genetic risk in consanguineous unions, especially when a disability such as hereditary deafness is involved.