Autosomal recessive blepharoptosis,cleft lip/palate,dental anomalies,and ectrodactyly

Fluorescence in situ hybridization (FISH) with α-satellite DNA probes was used to study whole-arm chromosome translocation products in a family in which the propositus was shown to have a monosomy 18p/trisomy 20p imbalance. By this approach, we show that the chromosome 18 α-satellite DNA block is split into 2 smaller units, whereas the chromosome 20 breakpoint is not included within the α-satellite DNA region. We found no evidence to suggest that this split α-satellite DNA region has reduced or impaired the function of the centromere or that it contributed to the phenotype of the propositus. The FISH technique critically demonstrated the involvement of a whole-arm translocation in this case and provided accurate identification of breakpoints, which was not possible with standard banding techniques. © Wiley-Liss, Inc.     

Parental consanguinity in two sibs with omodysplasia

Two sibs with omodysplasia were born to phenotypically normal but consanguineous parents. They had severe micromelic dwarfism, facial anomalies, and mental retardation. One had a congenital heart defect. The radiographic findings are typical: hypoplastic distal end of the humerus with radioulnar diastasis. Parental consanguinity and clinical manifestations in 2 sibs suggest autosomal recessive inheritance. © 1994 Wiley-Liss, Inc.     

A patient with novel MBOAT7 variant: The cerebellar atrophy is progressive and displays a peculiar neurometabolic profile

Mutations in the MBOAT7 gene have been described in 43 patients, belonging to 18 families, showing nonspecific clinical features (intellectual disability [ID], seizures, microcephaly or macrocephaly, and mild to moderate cerebellar atrophy) that make the clinical diagnosis difficult. Here we report the first Italian patient, a 22.5‐year‐old female, one of the oldest reported, born to apparently consanguineous parents. She shows severe ID, macrocephaly, seizures, aggressive outbursts, hyperphagia. We also documented progressive atrophy of the cerebellar vermis, that appeared not before the age of 7. The whole‐exome sequencing of the trio identified a novel homozygous variant c.1057_1058delGCinsCA (p.Ala353His) in the MBOAT7 gene. The variant is considered to be likely pathogenic, since it is absent from population database and it lies in a highly conserved amino acid residue. This disorder has a neurometabolic pathogenesis, implicating a phospholipid remodeling abnormalities. A brain hydrogen‐magnetic resonance spectroscopy (H‐MRS) examination in our patient disclosed a peculiar neurometabolic profile in the cerebellar hemispheric region. This new finding could address the clinical suspicion of MBOAT7‐related disorder, among the wide range of genetic conditions associated with ID and cerebellar atrophy. Moreover, the documented progression of cerebellar atrophy and the worsening of the disease only after some years open to the possibility of a therapeutic window after birth.     

Bloom's syndrome. XIX. Cytogenetic and population evidence for genetic heterogeneity

Cells with abnormally high rates of sister-chromatid exchange (SCE) are uniquely characteristic of Bloom's syndrome (BS). However, in one in five persons a minor population of cells with a low-SCE phenotype circulates in the blood. The origin and significance of the low-SCE cells in BS have never been understood, although they are assumed to arise by somatic mutation. In the present investigation, the enigmatic high-SCE/low-SCE mosaicism was investigated by comparing the incidence in several subpopulations of persons in the Bloom's Syndrome Registry who exhibit the two types of cells, and a striking negative correlation emerged: in persons with BS whose parents share a common ancestor, the case in approximately half of registered persons, low-SCE cells are found only rarely; conversely, the mosaicism occurs almost exclusively in persons with BS whose parents are not known to share a common ancestor. Because those who share a common ancestor are predominantly homozygous-by-descent at the mutated BS locus, the negative correlation is interpreted to mean that the emergence of low-SCE cells in BS in some way depends on the pre-existence of compound heterozygosity. A corollary to this is that BS is genetically heterogeneous.     

Genetic sperm defects and consanguinity.

BACKGROUND: The existence of a genetic component to human infertility has been suggested, although neither the specific abnormalities involved, nor their genetic mechanism of transmission, are currently defined. We have examined, by transmission electron microscopy (TEM), ejaculate from 1600 males with fertility problems. Among the subjects studied, we focused on a group of patients whose family histories revealed different degrees of consanguinity, in order to evaluate the relationship between consanguinity and particular sperm alterations. METHODS AND RESULTS: A total of 64 consanguineous individuals were identified. In this group, excluding two azoospermic patients, 17 patients (27%) were found to have well recognized genetic ultrastructural defects affecting their entire sperm population: eight subjects had spermatozoa with "stunted tails", four "detached tail" spermatozoa, two "Kartagener's syndrome", two "miniacrosome" and one "round headed" spermatozoa. Since these alterations affect the total sperm population and do not respond to medical treatment, they are suspected of having a genetic origin. The remaining group of 1506 non-consanguineous patients suffered from the same genetic defects in only 15 cases (<1%). CONCLUSIONS: From the data presented, it appears that some very peculiar and rare sperm defects may have a genetic basis since they occur more frequently in consanguineous patients, and are related to different degrees of consanguinity. Since the ejaculate of the remaining patients, both consanguineous and not, showed diverse types of ultrastructural sperm anomalies that did not affect the entire sperm population, they might represent pathologies lacking a genetic basis.     

Tuberculosis: a new look at an old disease

Mast cells are crucial effector cells evoking immune responses against bacterial pathogens. The positioning of mast cells at the host–environment interface, and the multitude of pathogen-recognition receptors and preformed mediator granules make these cells potentially the earliest to respond to an invading pathogen. In this review, the authors summarize the receptors used by mast cells to recognize invading bacteria and discuss the function of immune mediators released by mast cells in control of bacterial infection. The interaction of mast cells with other immune cells, including macrophages, dendritic cells and T cells, to induce protective immunity is highlighted. The authors also discuss mast cell-based vaccine strategies and the potential application in control of bacterial disease.     

Paternal Asthma is a Predictor for Childhood Asthma in the Consanguineous Families from the United Arab Emirates

Consanguinity is known to increase the burden of genetic disorders among offspring. However, the effect of consanguinity on a complex disorder like childhood asthma has not been studied previously. Therefore, we explored this relationship by studying the asthma prevalence in children between 6 and 14 years of age among the local Arab families of the United Arab Emirates (UAE) where consanguinity is known to be highly prevalent. A total of 1136 children from 295 families met our inclusion criteria. The prevalence of childhood asthma was higher among children in consanguineous families (43.3%) compared to non-consanguineous (22.6%, p < 0.001). There was a significant correlation between the degree of consanguinity and the number of asthmatic children per family (p = 0.0002). Girls from consanguineous families had proportionately more asthma (42.9%, p < 0.001) compared to boys (23.1%, p = 0.539).

Paternal asthma in consanguineous families increased asthma risk for both boys and girls (p = 0.021 for boys, p < 0.001 for girls), while maternal asthma had no significant impact on asthma in offspring. Prevalence of childhood asthma was significantly higher in consanguineous families. The significant asthma predictors for girls from the consanguineous families were the degree of consanguinity and paternal asthma. The only predictor for boys was paternal asthma. These interesting observations merit further studies on both larger samples and in other consanguineous communities for confirmation.     

Whole exome sequencing unravels disease‐causing genes in consanguineous families in Qatar

Whole exome sequencing (WES) has greatly facilitated the identification of causal mutations for diverse human genetic disorders. We applied WES as a molecular diagnostic tool to identify disease‐causing genes in consanguineous families in Qatar. Seventeen consanguineous families with diverse disorders were recruited. Initial mutation screening of known genes related to the clinical diagnoses did not reveal the causative mutations. Using WES approach, we identified the definitive disease‐causing mutations in four families: (i) a novel nonsense homozygous (c.1034C>G) in PHKG2 causing glycogen storage disease type 9C (GSD9C) in a male with initial diagnosis of GSD3; (ii) a novel homozygous 1‐bp deletion (c.915del) in NSUN2 in a male proband with Noonan‐like syndrome; (iii) a homozygous SNV (c.1598C>G) in exon 11 of IDUA causing Hurler syndrome in a female proband with unknown clinical diagnosis; (iv) a de novo known splicing mutation (c.1645+1G>A) in PHEX in a female proband with initial diagnosis of autosomal recessive hypophosphatemic rickets. Applying WES as a diagnostic tool led to the unambiguous identification of disease‐causing mutations in phenotypically complex disorders or correction of the initial clinical diagnosis in ?25% of our cases.