[Show abstract][Hide abstract] ABSTRACT: Background:
Heterozygous germline mutations in any of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, cause Lynch syndrome (LS), an autosomal dominant cancer predisposition syndrome conferring a high risk of colorectal, endometrial, and other cancers in adulthood. Offspring of couples where both spouses have LS have a 1:4 risk of inheriting biallelic MMR gene mutations. These cause constitutional MMR deficiency (CMMRD) syndrome, a severe recessively inherited cancer syndrome with a broad tumor spectrum including mainly hematological malignancies, brain tumors, and colon cancer in childhood and adolescence. Many CMMRD children also present with café au lait spots and axillary freckling mimicking neurofibromatosis type 1.
We describe our experience in seven CMMRD families demonstrating the role and importance of founder mutations and consanguinity on its prevalence. Clinical presentations included brain tumors, colon cancer, lymphoma, and small bowel cancer.
In children from two nonconsanguineous Ashkenazi Jewish (AJ) families, the common Ashkenazi founder mutations were detected; these were homozygous in one family and compound heterozygous in the other. In four consanguineous families of various ancestries, different homozygous mutations were identified. In a nonconsanguineous Caucasus/AJ family, lack of PMS2 was demonstrated in tumor and normal tissues; however, mutations were not identified.
CMMRD is rare, but, especially in areas where founder mutations for LS and consanguinity are common, pediatricians should be aware of it since they are the first to encounter these children. Early diagnosis will enable tailored cancer surveillance in the entire family and a discussion regarding prenatal genetic diagnosis.
Full-text · Article · Nov 2015 · Pediatric Blood & Cancer
[Show abstract][Hide abstract] ABSTRACT: Heterozygous germline mutations in any of the four mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2, cause Lynch syndrome (LS), an autosomal dominant cancer predisposition syndrome conferring a high risk of colorectal, endometrial and other cancers in adulthood. Offspring of couples where both spouses have LS have a 1:4 risk of inheriting biallelic MMR gene mutations. These cause constitutional MMR deficiency (CMMRD) syndrome, a severe recessively inherited cancer syndrome with a very broad tumor spectrum including mainly hematological malignancies, brain tumors and colon cancer in childhood and adolescence. Many CMMRD children also present with café au lait spots and axillary freckling mimicking Neurofibromatosis type 1 (NF1).
We describe here our experience in Israel with five CMMRD families. The clinical presentation included brain tumors at ages 2-19 years, colon cancer at ages 9-20 years, one patient with lymphoma at age 6 years and one patient with small bowel cancer at age 22 years. In children from two non-consanguineous Ashkenazi families the common Ashkenazi founder mutations were detected homozygously in one and compound heterozygously in another. In three consanguineous families of Jewish Iranian, Bedouin and Palestinian ancestries, different homozygous mutations were identified.
CMMRD is a rare syndrome, but especially in areas where founder mutations for LS and consanguinity are common pediatricians should be aware of it since they are the first to encounter these children, an early diagnosis will enable tailored cancer surveillance in the entire family and a discussion regarding the options for prenatal genetic diagnosis.
No preview · Article · Sep 2015 · Pediatric Blood & Cancer
[Show abstract][Hide abstract] ABSTRACT: Genetic syndromes involving both brain and eye abnormalities are numerous and include syndromes such as Warburg micro syndrome, Kaufman oculocerebrofacial syndrome, Cerebro-oculo-facio-skeletal syndrome, Kahrizi syndrome and others. Using exome sequencing, we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families, all originating from the same village. The protein encoded by MED25 belongs to Mediator complex or MED complex, which is an evolutionary conserved multi-subunit RNA polymerase II transcriptional regulator complex. The MED25 point mutation is located in the von Willebrand factor type A (MED25 VWA) domain which is responsible for MED25 recruitment into the Mediator complex; co-immunoprecipitation experiment demonstrated that this mutation dramatically impairs MED25 interaction with the Mediator complex in mammalian cells.
[Show abstract][Hide abstract] ABSTRACT: Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by progressive muscle weakness. It is caused by a mutation in the survival motor neuron gene 1 (SMN1) gene. SMA with respiratory distress 1 (SMARD1), an uncommon variant of infantile SMA also inherited in an autosomal recessive manner, is caused by mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene. We carried out genetic carrier screening among the residents of an isolated Israeli Arab village with a high frequency of SMA in order to identify carriers of SMA type I and SMARD1. During 2006, 168 women were tested for SMA, of whom 13.1% were found to be carriers. Of 111 women tested for SMARD1, 9.9% were found to be carriers. Prenatal diagnosis was performed in one couple where both spouses were carriers of SMARD1; the fetus was found to be affected, and the pregnancy was terminated. To the best of our knowledge, this is the first example of the establishment of a large-scale carrier-screening program for SMA and SMARD1 in an isolated population. SMA has a carrier frequency of 1:33-1:60 in most populations and should be considered for inclusion in a population-based genetic-screening program.
[Show abstract][Hide abstract] ABSTRACT: Nonsyndromic mental retardation (NSMR) is the diagnosis of exclusion in mentally retarded individuals without additional abnormalities. We have recently identified a protein-truncating mutation, G408fsX437, in the gene CC2D1A on chromosome 19p13.12 in nine consanguineous Israeli Arab families with severe autosomal recessive NSMR, and have developed a comprehensive prevention program among the at-risk population in the village. The subjects tested were healthy women who were invited to undergo the genetic screening test as a part of their routine pregnancy monitoring. One hundred and seventeen subjects reported a family history positive for mental retardation. We tested 524 pregnant or preconceptional women and found 47 carriers (approximately 1/11), whose spouses were then recommended to undergo testing. We identified eight carrier couples, who were given genetic counseling and offered prenatal diagnosis. Of all the marriages, 28.6% were consanguineous; 16.5% of the total were between first cousins. The high prevalence of the mutation can be explained both by the founder effect owing to the generally high consanguinity rate among the inhabitants of the village, and also because two families with excessive numbers of mentally retarded offspring were unacceptable as marriage partners by the rest of the families. This is the first example of the establishment of a large-scale genetic screening program for autosomal recessive NSMR, which was made possible owing to the high frequency of the specific causative mutation in this isolated population.
Full-text · Article · Mar 2007 · European Journal of HumanGenetics
[Show abstract][Hide abstract] ABSTRACT: A case of prenatally diagnosed trisomy 11 mosaicism with a normal outcome is reported and the medical literature on prenatal detection of this finding is reviewed.
Proportion of cells with trisomy 11 was evaluated in amniocytes, fetal blood lymphocytes, newborn fibroblasts and urinary epithelial cells. Karyotype studies and fluorescence in situ hybridization analysis using the 11q13LS1 CCND1 probe were performed.
Trisomy 11 level III mosaicism of 26% was detected in amniotic fluid cells. Periumbilical blood sampling showed a normal fetal karyotype. No fetal structural abnormalities were noted on ultrasound scan. The infant was spontaneously delivered and had normal physical findings at birth. No evidence of trisomic cells was found on extensive postnatal evaluation, implying an extraembryonic origin. Molecular analysis excluded uniparental disomy of chromosome 11. At 1 year of age, the baby is developing normally.
Only three reports on trisomy 11 mosaicism identified at amniocentesis have been published previously, all with a normal outcome. Additional cases of prenatally diagnosed mosaicism for trisomy 11 are necessary to assess more accurately the clinical significance of this finding.
No preview · Article · Sep 2006 · Prenatal Diagnosis
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to identify the gene causing autosomal recessive infantile bilateral striatal necrosis.
We have mapped the disease gene in the candidate region to approximately 230kb on 19q13.33 in 8 interrelated families including a total of 12 patients and 39 unaffected individuals.
Sequencing of the nup62 gene showed a missense mutation causing a change from glutamine to proline (Q391P) in all the patients, producing a substitution from a polar, hydrophilic residue to a nonpolar, neutral residue. All the other 12 candidate genes were sequenced, and no pathogenic sequence changes were found. Comparisons of p62 protein sequences from diverse species indicate that glutamine at position 391 is highly conserved. Five prenatal diagnoses were performed in three at-risk families.
This is the second example of a nuclear pore complex protein causing mendelian disease in humans (the first one is triple A syndrome). Our findings suggest that p62 has a cell type-specific role and is important in the degeneration of the basal ganglia in humans.
Full-text · Article · Aug 2006 · Annals of Neurology
[Show abstract][Hide abstract] ABSTRACT: The molecular basis of autosomal recessive non-syndromic mental retardation (NSMR) is poorly understood, mostly owing to heterogeneity and absence of clinical criteria for grouping families for linkage analysis. Only two autosomal genes, the PRSS12 gene on chromosome 4q26 and the CRBN on chromosome 3p26, have been shown to cause autosomal recessive NSMR, each gene in only one family.
To identify the gene causing autosomal recessive NSMR on chromosome 19p13.12.
The candidate region established by homozygosity mapping was narrowed down from 2.4 Mb to 0.9 Mb on chromosome 19p13.12. A protein truncating mutation was identified in the gene CC2D1A in nine consanguineous families with severe autosomal recessive NSMR. The absence of the wild type protein in the lymphoblastoid cells of the patients was confirmed. CC2D1A is a member of a previously uncharacterised gene family that carries two conserved motifs, a C2 domain and a DM14 domain. The C2 domain is found in proteins which function in calcium dependent phospholipid binding; the DM14 domain is unique to the CC2D1A protein family and its role is unknown. CC2D1A is a putative signal transducer participating in positive regulation of I-kappaB kinase/NFkappaB cascade. Expression of CC2D1A mRNA was shown in the embryonic ventricular zone and developing cortical plate in staged mouse embryos, persisting into adulthood, with highest expression in the cerebral cortex and hippocampus.
A previously unknown signal transduction pathway is important in human cognitive development.
Full-text · Article · Apr 2006 · Journal of Medical Genetics
[Show abstract][Hide abstract] ABSTRACT: Fragile-X syndrome is caused by an unstable CGG trinucleotide repeat in the FMR1 gene at Xq27. Intermediate alleles (51-200 repeats) can undergo expansion to the full mutation on transmission from mother to offspring. To evaluate the effectiveness of a fragile-X carrier-screening program, we tested 14,334 Israeli women of child-bearing age for fragile-X carrier status between 1992 and 2000. These women were either preconceptional or pregnant and had no family history of mental retardation. All those found to be carriers of premutation or full-mutation alleles were offered genetic counseling and also prenatal diagnosis, if applicable. We identified 207 carriers of an allele with >50 repeats, representing a prevalence of 1:69. There were 127 carriers with >54 repeats, representing a prevalence of 1:113. Three asymptomatic women carried the fully mutated allele. Among the premutation and full-mutation carriers, 177 prenatal diagnoses were performed. Expansion occurred in 30 fetuses, 5 of which had an expansion to the full mutation. On the basis of these results, the expected number of avoided patients born to women identified as carriers, the cost of the test in this study (U.S. $100), and the cost of lifetime care for a mentally retarded person (>$350,000), screening was calculated to be cost-effective. Because of the high prevalence of fragile-X premutation or full-mutation alleles, even in the general population, and because of the cost-effectiveness of the program, we recommend that screening to identify female carriers should be carried out on a wide scale.
Full-text · Article · Sep 2001 · The American Journal of Human Genetics
[Show abstract][Hide abstract] ABSTRACT: Fragile X syndrome (Fra X) is the most common heritable disease accounting for mental retardation and is caused by an expanded CGG repeat in the first exon of the FMR1gene. Previous studies have shown an increased fertility rate among fragile X carrier mothers and a preponderance of mentally retarded boys among the male offspring. In this study, we examined the transmission of the intermediate allele in the lower range of CGG repeats in carrier mothers found randomly in a screening program of the normal population. We tested 10,587 healthy women with no family history of mental retardation and identified 138 (1.3%) who were carriers of the intermediate allele (51-200 CGG repeats). Of these, 107 underwent prenatal testing during 108 pregnancies for Fra X in the fetus. Of the 108 pregnancies, the abnormal allele was transmitted in 67 (segregation ratio = 0.62, P < 0.012). We found a significant increase in the transmission of the abnormal allele by mothers who had between 51 and 60 repeats (segregation ratio = 0.69 [P < 0.007] for the group with 51-55 repeats, and 0.74 [P < 0.04] for the group with 56-60 repeats), but no increase by mothers who had more than 61 repeats. This suggests a genetic advantage for the abnormal allele in the 51- to 60-repeat range.
No preview · Article · Jul 2000 · American Journal of Medical Genetics