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PubMed2003

van den Ende-Gupta syndrome of blepharophimosis, arachnodactyly, and congenital contractures: clinical delineation and recurrence in brothers.

We describe two Hispanic brothers born to unrelated parents with van den Ende-Gupta syndrome (VDEGS), a distinctive combination of characteristic dysmorphic features, skeletal abnormalities, and cerebellar hyperplasia. This syndrome was previously delineated by van den Ende et al. [1992: Am J Med Genet 42:467-469] and Gupta et al. [1995: J Med Genet 32:809-812], with additional reports by Phadke et al. [1998: Am J Med Genet 77:16-18] and Bistritzer et al. [1993: Clin Genet 44:15-19]. This is the fifth report of VDEGS, which is characterized by blepharophimosis, narrow nose with hypoplastic alae nasi, hypoplastic maxilla, everted lower lip, slender and elongated hands and feet, arachnodactyly, self-limiting joint contractures, and distinctive skeletal findings. This report of affected siblings, and a previous report of double second cousins born to consanguineous parents [Bistritzer et al. [1993: Clin Genet 44:15-19]], suggests autosomal recessive inheritance. This brings to eight, the total number of reported cases, derived from six families, three of which are consanguineous. It is important to distinguish VDEGS from Marden-Walker syndrome (MWS) since both syndromes include blepharophimosis, arachnodactyly, and congenital contractures. Both syndromes are inherited in an autosomal recessive fashion, but VDEGS lacks severe mental retardation, serious brain malformations, microcephaly, failure to thrive, and severe joint limitation, which are consistently present in MWS. Of particular importance, MWS may be associated with cerebellar malformations such as Dandy-Walker malformation, while the brothers reported herein with VDEGS both demonstrated distinctive cerebellar enlargement, a new finding for this disorder. While, congenital contractures with arachnodactyly are features commonly seen in several other delineated syndromes, such as congenital contractural arachnodactyly (CCA) syndrome, characteristic facial features (blepharophimosis, narrow nose with ocular hypertelorism, prominent ears, and everted lower lip), distinguish VDEGS from other syndromes associated with CCA, including CCA.

Blepharophimosis↗

PubMed2003

Analysis of 40 sporadic or familial neonatal and pediatric cases with severe unexplained respiratory distress: relationship to SFTPB.

We have analyzed surfactant protein B (SP-B) and its encoding gene (SFTPB, MIM 178640) in 40 unrelated pediatric patients with unexplained respiratory distress (URD). There was high consanguinity (eight kindreds) and an underlying autosomal recessive trait could be inferred in most cases, with overall high sex ratio (32/17) suggesting proband's gender to impact on penetrance. The clinical/biological presentations fitted into three major nosologic frameworks. I: SP-B deficiency (nine probands), complete or incomplete, with homozygous/compoundly heterozygous mutations identified (six probands), including one from the population isolate of Réunion Island (496delG). In addition, there was a consanguineous kindred in which incomplete deficiency was unambiguously unlinked to SFTPB. II: pulmonary alveolar proteinosis (PAP, 19 probands), with typical storage of PAS-positive material within the alveoli with foamy macrophages and variable interstitial reaction, which was diagnosed in most patients from Réunion Island. In contrast to previously published findings, mutation and/or segregation analyses excluded SFTPB as a disease locus, although slight metabolic derangement related to SP-B and/or mild SFTPB changes could somehow contribute to disease. III: URD without evidence for SP-B deficiency or PAP (12 probands), equally unlinked to SFTPB, although a single patient had a possibly causal, maternally-derived, heterozygous genetic change (G4521A). The population frequency of five known and four novel SNPs was studied, providing as many potential markers for pulmonary disease related to SFTPB. Overall, URD was found to be heterogeneous, both phenotypically and genetically, even in population isolates where a founder effect might have been expected. When disease loci are identified, patient genotyping will be crucial as a diagnostic aid, for devising proper treatment, and as a basis for genetic counseling.

Amino Acid Sequence↗

PubMed2003

Relative prevalence of malformations at birth among different religious communities in Israel.

The aim of this research was to determine the relative prevalence at birth of major malformations among the different religious communities in Israel as a way to better understand their causes. We collected data on malformations present among liveborn infants in a 10-year period from the national registry of birth defects according to the religious affiliation. In a total of 1,203,763 liveborn infants, the prevalence of major malformations was in a similar range among Jews and Christians and much higher among Muslim and Druze. These observations may be explained by differences between these communities, in particular, the rates of consanguinity and of therapeutic abortions. The Muslim and Druze communities in Israel are those with the highest consanguinity rates and the lowest rates of termination of pregnancies when a malformation is diagnosed. Analysis of the differences in the rate of malformations at birth in different communities is important for Public Health planning. It may also help to delineate causes and serve as the basis for research.

Christianity↗

PubMed2004

Phenotypic manifestations of the OCTN2 V295X mutation: sudden infant death and carnitine-responsive cardiomyopathy in Roma families.

In two non-consanguineous Hungarian Roma (Gypsy) children who presented with cardiomyopathy and decreased plasma carnitine levels, we identified homozygous deletion of 17081C of the SLC22A5 gene that results in a frameshift at R282D and leads ultimately to a premature stop codon (V295X) in the OCTN2 carnitine transporter. Carnitine treatment resulted in dramatic improvement of the cardiac symptoms, echocardiographic, and EKG findings in both cases. Family investigations revealed four sudden deaths, two of them corresponded to the classic SIDS phenotype. In postmortem tissue specimens available from three of them we could verify the homozygous mutation. In liver tissue reserved from two patients lipid droplet vacuolization could be observed; the lipid vacuoles were located mainly in the peripherolobular regions of the acini. In the heart tissue signs of generalized hypertrophy and lipid vacuoles were seen predominantly in the subendocardial areas in both cases; some aggregates of smaller lipid vacuoles were separated, apparently by membranes. Review of all OCTN2 deficiency cases reported so far revealed that this is the first presentation of histopathology in classic familial sudden infant death syndrome (SIDS) with an established SLC22A5 mutation. In addition to the two affected homozygous cardiomyopathic children and three homozygous sudden death patients, the genetic analysis in 25 relatives showed 14 carriers. The mutant gene derived from five non-consanguineous grandparents, each of them having 6-14 brothers and sisters. This alone suggests a wide ancestral spread of the mutation in certain Roma subpopulations.

Amino Acid Sequence↗

PubMed2005

Familial recurrence of heart defects in subjects with congenitally corrected transposition of the great arteries.

Familial recurrence of congenitally corrected transposition of the great arteries (CCTGA) is considered uncommon. Most of the previous familial studies involved a small number of patients and referred to all situs and looping anomalies including single ventricle, heterotaxia, and other cardiac defects different from CCTGA. We performed a large, consecutive clinical case series study in order to detect the recurrence of congenital heart defects in families of children with the classic form of CCTGA. From January 1997 through December 2004, 102 consecutive patients with CCTGA were evaluated in four institutions. There were 59 male (57.8%) and 43 female (42.2%). Mean age was 8.6 +/- 7.8 years. Eighty-eight patients (86.3%) had situs solitus of the atria, 14 (13.7%) situs inversus. The cardiac and extracardiac anomalies among relatives and the patterns of familial recurrence were investigated. Relatives with congenital heart defects were found in 16/102 families (15.7%). Transposition of the great arteries (TGA) was the most common recurrent defect (6/102 families). Consanguinity was identified in the parents of three probands. Six probands had an unaffected twin-sib. Recurrence risks for congenital heart defects were calculated at 5.2% (6/116) for siblings. In conclusion, CCTGA is not always sporadic in families. The pattern of inheritance, the presence of consanguinity among parents and the recurrence of situs inversus could suggest, in some families, an autosomal recessive mechanism with similarities with that occurring in some pedigrees with heterotaxia. The recurrence of TGA and CCTGA in the same family suggests a pathogenetic link between these two anatomically different malformations.

Family Health↗

PubMed1987

Inherited deficiency of erythrocyte complement receptor type 1 does not cause susceptibility to systemic lupus erythematosus.

There is a deficiency of complement receptor type 1 (CR1) on the erythrocytes of patients with systemic lupus erythematosus (SLE). This receptor is involved in the processing of immune complexes. Whether the deficiency is inherited or acquired has been the subject of controversy. A restriction fragment length polymorphism (RFLP), identified using a complementary DNA probe for CR1, has been correlated with the numeric expression of CR1 on normal erythrocytes. The gene frequency for the 2 alleles defined by this RFLP was compared in 44 patients with SLE (from 42 families), 43 of their consanguineous relatives, and 50 nonrelated normal subjects. The gene frequency for the alleles correlating with high and low expression of CR1 was 0.73 and 0.27, respectively, in the normal subjects. The gene frequency was not significantly different in the SLE patients. However, the SLE patients expressed fewer CR1 molecules per erythrocyte within each genotype, compared with normal subjects and compared with their consanguineous relatives. The low allele for numeric expression of CR1 on erythrocytes is not a disease susceptibility gene for SLE.

Alleles↗

PubMed1993

Molecular studies of mitochondrial acetoacetyl-coenzyme A thiolase deficiency in the two original families.

We describe mutations identified in stored skin fibroblast cell lines from two original probands (JB and JM), first reported with 2-methylacetoacetic aciduria, and shown later to have a deficiency of the K(+)-activated enzyme, mitochondrial acetoacetyl-coenzyme A thiolase (T2). JB is homozygous for a 4-base insertion (GCAG) which is derived mutation. The primary mutation is an AG/gt to AG/gc transition at the 5'-splice-junction site in intron 11. An alternative splice site 4 bp downstream (Ggcag/gt) is used which causes a frame shift and replaces 39 C-terminal residues by 70 nonfunctional residues. JM is homozygous for a mutation in the translation-initiation codon (ATG to AAG). By expression analyses the JB mutation (IVS11nt2) causes an unstable T2 polypeptide and the JM mutation (M1K) severely impairs T2 mRNA translation. The JB allele associates with Dutch ancestry (no consanguinity) and the JM allele with Chilean ancestry (distant consanguinity).

Acetyl-CoA C-Acetyltransferase↗

PubMed2003

Mutations spectrum of GNE in hereditary inclusion body myopathy sparing the quadriceps.

Hereditary Inclusion Body Myopathy (HIBM) is a unique group of neuromuscular disorders characterized by adult onset and a typical muscle pathology. We have recently identified the gene encoding for a bifunctional enzyme, UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamine kinase (GNE), as the mutated gene in the prototype form of the disease presenting quadriceps sparing, particularly common in Middle Eastern Jews. Interestingly, we have identified the homozygous M712T Middle Eastern Jewish mutation also in two unrelated Middle Eastern Moslem families. We have also evaluated the involvement of GNE in several families from worldwide non-Jewish ethnic origins presenting symptoms similar to the Middle Eastern HIBM prototype. A total of 14 GNE mutations were identified (one nonsense and 13 missense), of which six are novel: an homozygous missense mutation in a consanguineous family from Italy and in a non consanguineous family from USA, and distinct compound heterozygotes in families from Germany, Italy, Ireland, Bahamas, USA and East India. This study brings to 17 the number of reported GNE mutations in quadriceps sparing myopathy, occurring either in the epimerase or the kinase domain of the enzyme. The mechanism leading to this unique phenotype still remains to be elucidated.

Adolescent↗

PubMed2004

Loss-of-function mutations in cathepsin C in two families with Papillon-Lefèvre syndrome are associated with deficiency of serine proteinases in PMNs.

Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disease that involves severe periodontitis and hyperkeratosis of the hand palms and foot soles. Recently it was found that PLS patients carry loss-of-function mutations in the gene encoding cathepsin C (CTSC). In the present study we have analyzed the CTSC gene in two unrelated families with PLS. In the first non-consanguineous family, mutation analysis revealed the previously reported c.815G>C/p.R272P mutation. The second consanguineous family displayed a c.1213C>A mutation which resulted in the novel mutation p.H405N and is the first mutation described in the active site of the enzyme. The PLS patients had, next to the absence of cathepsin C activity in polymorphonuclear leukocytes (PMNs), no activity of the three serine proteinases elastase, cathepsin G and proteinase 3. Serine proteinases are supposed to be important in both the innate and adaptive immune systems. Their absence in PLS patients could explain the inadequate defense to periodontal infection.

Amino Acid Sequence↗

PubMed1989

A leucine-to-proline mutation in the insulin receptor in a family with insulin resistance.

We have determined the primary structure of a mutant insulin receptor of a leprechaun patient born from a consanguineous marriage. A characteristic feature of leprechaunism is an extreme resistance to insulin. In this patient the insulin resistance seems to result from an observed lack of insulin binding to intact cells. Solubilization of cells in non-ionic detergents leads to the appearance of insulin receptors which can bind insulin. However, the insulin-stimulated autophosphorylation of the receptor's beta subunit is markedly reduced. Cloning and sequencing of cDNA derived from insulin receptor mRNA of this patient revealed a leucine-to-proline mutation at position 233 in the alpha subunit. By means of DNA amplification we found that the patient is homozygous for this mutation and that the parents and two grandparents from the consanguineous line are heterozygous. The heterozygous individuals all show decreased insulin binding to cultured fibroblasts. In addition, they are mildly insulin resistant in vivo. These observations show a linkage between the leucine-to-proline mutation and the observed insulin resistance in this family. We therefore conclude that the mutation in the homozygous form is responsible for the extreme insulin resistance in the leprechaun patient. The mutation for the first time characterizes a region in the insulin receptor which seems to be involved in transmitting the insulin binding signal to the tyrosine kinase domain.

Cells, Cultured↗

PubMed2001

Attitude of Saudi families affected with hemoglobinopathies towards prenatal screening and abortion and the influence of religious ruling (Fatwa).

Hemoglobinopathies are common inherited disorders in Saudi Arabia. Prenatal diagnosis for such diseases is specific and sensitive but not yet implemented in Saudi Arabia. Saudis are Muslims with a very high rate of consanguinity and inherited genetic disorders. To examine the attitude of Saudi families affected with hemoglobinopathies towards prenatal diagnosis and abortion, and to evaluate the effect of education on religious ruling on such attitudes, 32 families were interviewed using a pre-structured questionnaire. The majority accepted prenatal diagnosis (81.3%). The attitude towards abortion was greatly affected by religious values. Education about religious ruling significantly affected parents' attitude towards accepting abortion and prenatal diagnosis. No other factors were found to influence the outcome. Although the majority of families received some kind of formal genetic counseling [23/32 (71.9%)], none of them was informed about the possibility of prenatal or preimplantation diagnosis prior to the interview. Therefore for prevention of genetic disorders, the emphasis in countries with a vast majority of Muslims such as Saudi Arabia has probably to be placed on public awareness about genetic risks, the risk of consanguinity, availability of services, and so on, while at the same time taking into consideration the religious beliefs and education of the target population

Abortion, Induced↗

PubMed1998

The autosomal recessive Kenny-Caffey syndrome locus maps to chromosome 1q42-q43.

Kenny-Caffey syndrome (KCS) is an osteosclerotic bone dysplasia with associated hypocalcemia and ocular abnormalities. Both autosomal dominant (MIM127000) and autosomal recessive (MIM244460) inheritance patterns have been described. Using eight consanguineous Kuwaiti kindreds, a genome-wide search for linkage to the gene causing the autosomal recessive form of KCS was performed with polymorphic short tandem repeat markers. Significant linkage to a locus situated at chromosome 1q42 --> q43 with a maximal two-point lod score of 13.30 with marker D1S2649 was obtained. Haplotype analysis of flanking markers identified recombination events defining the KCS locus to a region between markers D1S2800 on the centromeric boundary and D1S2850 on the telomeric boundary, an approximately 4-cM interval. All affected individuals in these unrelated kindreds were homozygous for identical alleles at markers D1S2649 and D1S235, suggesting a single ancestral mutation underlying the disease in these families. Haploinsufficiency at 22q11, reported in another consanguineous KCS kindred, was not documented in these families.

Abnormalities, Multiple↗

PubMed1987

The genetic consequences of primate social organization: a review of macaques, baboons and vervet monkeys.

Primates, as long-lived, iteroparous, socially complex mammals, offer the opportunity to assess the effects of behavior and demography on genetic structure. Because it is difficult to obtain tissue samples from wild primate populations, research in this area has largely been confined to terrestrial and semi-terrestrial old world monkeys (e.g., rhesus and Japanese macaques, vervets and several subspecies of baboons). However, these species display a multi-male, multi-female social structure commonly found in many other primate and non-primate mammals. Electrophoretic analyses of blood proteins from individually recognized and/or marked wild Himalayan rhesus monkeys, themselves the subject of long-term behavioral and demographic research, have begun to reveal the genetic consequences of such phenomena as social group fission, male-limited dispersion, non-consanguineous mating patterns, and agonistically defined male dominance. Specifically, rhesus social groups, consisting primarily of clusters of maternal relatives, appear to be non-random samples of a population's genotypes and genes. The genetic effects of social group fission are highly dependent on each group's size, demographic structure, and average degree of relatedness. In all cases fission contributes to the degree of intergroup genetic differentiation. Male-limited dispersion appears both to retard genetic differentiation between social groups and to lead to mating patterns that result in an avoidance of consanguinity. Groups, therefore, appear to be genetically outbred. Comparing these results with studies of other free-ranging or wild cercopithecines allows several generalizations: (a) genetic variation seems to be evenly distributed throughout each local population of multi-male social groups; (b) social groups, however, because they contain clusters of relatives, are distinctive in their specific frequencies of genes; (c) the degree of genetic differentiation between a population's social groups, because of the effects of social group fission and non-deterministic forms of male dispersal, is somewhat greater than expected on the basis of migration rates alone; and (d) the asymmetrical pattern of dispersion with respect to sex effectively precludes inbreeding in any one social group or the population as a whole. These observations have important implications for understanding the unusually rapid rates of evolution among the primates.

Animals↗

PubMed2004

Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome.

AIMS/HYPOTHESIS: Neonatal diabetes is a rare disease with several identified molecular aetiologies. Despite associations with other malformations, neonatal diabetes with intestinal and biliary anomalies has not been described. The current study aims to describe a new syndrome, and to examine a possible link with one of three genes known to cause neonatal diabetes. METHODS: Five clinical cases are described. Immunohistochemical staining for pancreatic islet hormones was performed on three of the infants. DNA from one infant was analysed for abnormalities of the PLAGL-1 (ZAC), glucokinase and PDX-1 (IPF-1) genes. RESULTS: Five infants (two sibling pairs from two families, and an isolated case) presented with neonatal diabetes, hypoplastic or annular pancreas, jejunal atresia, duodenal atresia and gall bladder aplasia or hypoaplasia. One sibling pair was born to consanguineous parents. One patient with a milder form is surviving free of insulin. Four children died in the first year of life despite aggressive medical management. Pancreatic immunohistochemistry revealed few scattered chromogranin-A-positive cell clusters but complete absence of insulin, glucagon and somatostatin. Exocrine histology was variable. In one case from the consanguineous family, molecular analysis showed no duplication or uniparental isodisomy of PLAGL-1 at 6q24, no contiguous gene deletion involving the glucokinase gene, and no mutation in the coding sequences or splice sites of PDX-1. CONCLUSIONS/INTERPRETATION: This combination of multiple congenital abnormalities has not been previously described and probably represents a new autosomal recessive syndrome involving a genetic abnormality that interferes with normal islet development and whose aetiology is as yet unknown.

Abnormalities, Multiple↗

PubMed1997

Familial Mediterranean fever in children: report of a large series and discussion of the risk and prognostic factors of amyloidosis.

UNLABELLED: Familial Mediterranean fever (FMF) is a genetically transmitted disease characterized by recurrent attacks of fever and serositis. The most important complication of this disease is the development of amyloidosis. We present our analysis of 425 FMF patients without and 180 with amyloidosis (123 FMF having amyloidosis type 1 and 57 FMF having amyloidosis type II). The male female ratio was higher in the amyloidosis population (111/69) when compared to the FMF population (225 200) (P = 0.048). Consanguinity rate was the same among FMF and amyloidosis groups. However, a family history of amyloidosis was significantly more frequent in the amyloidosis group (P = 0.00001). Multivariate analysis has revealed that in FMF patients, the presence of a family history of amyloidosis plus consanguinity has a 6.04 fold increased risk of amyloidosis (P < 0.0001). The 5-year chronic renal failure free survival was 43.1% and 18.7% in type I and type II amyloidosis, respectively. The time interval to develop chronic renal failure after the development of amyloidosis was 4.8 in type I and 3.0 years in type II. respectively. We found ten cases of Henoch-Schönlein Purpura and nine of polyarteritis nodosa among our patients. The significance of the association between FMF and vasculitis awaits to be clarified. Among the FMF patients put on colchicine therapy (435), only 10 (2.3%) have developed amyloidosis confirming that this drug protects from amyloidosis. CONCLUSION: Since the presence of a familial history of amyloidosis has been defined as the most important risk factor in the development of amyloidosis, we suggest that additional genetic factors may be operative in the development of amyloidosis.

Amyloidosis↗

PubMed2003

The origins and genetic structure of three co-resident Chinese Muslim populations: the Salar, Bo'an and Dongxiang.

A genome-based investigation of three Muslim populations, the Salar, Bo'an, and Dongxiang, was conducted on 212 individuals (148 males, 64 females) co-resident in Jishisan County, a minority autonomous region located in the province of Gansu, PR China. The Salar are believed to be of Turkic origin, whereas the Bo'an and Dongxiang both speak Mongolian. Biparental dinucleotide markers on chromosomes 13 and 15 indicated elevated mean homozygosity in the Salar (0.32), Bo'an (0.32), and Dongxiang (0.27), equivalent to inbreeding coefficients ( F(is) ) of 0.16; 0.12; 0.01, confirming varying levels of endogamous and consanguineous marriage in all three communities. Y-chromosome unique event polymorphisms (UEPs) showed that males in the three communities shared common ancient origins, with 80-90% of haplotypes in common. However, the high levels of community-specific Y-chromosome STR haplotypes strongly suggested the action(s) of founder effect, genetic drift and preferential consanguinity during more recent historical time. By comparison with the marked inter-community differentiation revealed by the Y-chromosome STRs (29.4%), the mtDNA data indicated similarity between the female lineages of each community with just 1.2% inter-community variation. The combined use of these different marker systems gives an in-depth historical perspective, and provides evidence of past inter-marriage between genetically diverse male founders of each community and Han Chinese females with subsequent community endogamy.

Adolescent↗

PubMed2003

Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria.

Familial renal glucosuria is an inherited renal tubular disorder. A homozygous nonsense mutation in the SLC5A2 gene, encoding the sodium/glucose co-transporter SGLT2, has recently been identified in an affected child of consanguineous parents. We now report novel compound heterozygous mutations in the son of non-consanguineous parents. One allele has a p.Q167fsX186 mutation, which is expected to produce a truncated protein, and the other a p.N654S mutation involving a highly conserved residue. These findings confirm that mutations in the SLC5A2 gene are responsible for recessive renal glucosuria.

Adult↗

PubMed2005

Localisation of merosin-positive congenital muscular dystrophy to chromosome 4p16.3.

The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders, which present within the first 6 months of life with hypotonia, muscle weakness and contractures, associated with dystrophic changes on skeletal muscle biopsy. We have previously reported a large consanguineous family segregating merosin-positive congenital muscular dystrophy, in which involvement of known CMD loci was excluded. A genome-wide linkage search of the family conducted using microsatellite markers spaced at 10-Mb intervals failed to identify a disease locus. A second scan using a high-density SNP array, however, permitted a novel CMD locus on 4p16.3 to be identified (multipoint LOD score 3.4). Four additional consanguineous CMD families with a similar phenotype were evaluated for linkage to a 4.14-Mb interval on 4p16.3; however, none showed any evidence of linkage to the region. Our findings further illustrate the utility of highly informative SNP arrays compared with standard panels of microsatellite markers for the mapping of recessive disease loci.

Chromosome Disorders↗