Prenatal Diagnosis of Fragile X: Can a Full Mutation Allele in the FMR1 Gene Contract to a Normal Size?

Here we describe a case of a prenatal diagnosis of a male fetus that inherited the unstable allele from his full mutation mosaic mother (29, 160, >200 CGG repeats) reduced to a normal size range (19 CGG repeats). Haplotype analysis showed that the fetus 19 CGG repeats allele derived from the maternal unstable allele which was inherited from his maternal grandmother. No size mosaicism was detected by testing the DNA from in vitro cultured samples, including seventh passage culture as well as from two amniocentesis samples. Sequence analysis confirmed that the allele was 19 CGG repeats long. Methylation assay showed no methylation. Although none of the techniques used in this study can provide with absolute certainty the diagnosis, the results strongly indicate the presence in the fetus of an allele with a CGG repeat number in the normal range. Because this is a prenatal diagnosis case, the crucial question is whether the 19 CGG allele derived from the maternal unstable expanded allele, which contracted to the normal range, became a normal stable allele or a normal unstable allele which could expand in the next generation. It is also possible that allele size mosaicism of the FMR1 gene that went undetected exists. Because this is a prenatal diagnosis case, we cannot with certainty exclude the presence of an undetected expanded allele of the FMR1 gene, in addition to the 19 CGG allele derived from an unstable expanded allele, which contracted to the normal range

Prenatal Diagnosis of Fragile X: Can a Full Mutation Allele in the FMR1 Gene Contract to a Normal Size?

Here we describe a case of a prenatal diagnosis of a male fetus that inherited the unstable allele from his full mutation mosaic mother (29, 160, >200 CGG repeats) reduced to a normal size range (19 CGG repeats). Haplotype analysis showed that the fetus 19 CGG repeats allele derived from the maternal unstable allele which was inherited from his maternal grandmother. No size mosaicism was detected by testing the DNA from in vitro cultured samples, including seventh passage culture as well as from two amniocentesis samples. Sequence analysis confirmed that the allele was 19 CGG repeats long. Methylation assay showed no methylation. Although none of the techniques used in this study can provide with absolute certainty the diagnosis, the results strongly indicate the presence in the fetus of an allele with a CGG repeat number in the normal range. Because this is a prenatal diagnosis case, the crucial question is whether the 19 CGG allele derived from the maternal unstable expanded allele, which contracted to the normal range, became a normal stable allele or a normal unstable allele which could expand in the next generation. It is also possible that allele size mosaicism of the FMR1 gene that went undetected exists. Because this is a prenatal diagnosis case, we cannot with certainty exclude the presence of an undetected expanded allele of the FMR1 gene, in addition to the 19 CGG allele derived from an unstable expanded allele, which contracted to the normal range

Fragile-X Carrier Screening and the Prevalence of Premutation and Full-Mutation Carriers in Israel

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

Autosomal Recessive Ichthyosis with Hypotrichosis Caused by a Mutation in ST14, Encoding Type II Transmembrane Serine Protease Matriptase

In this article, we describe a novel autosomal recessive ichthyosis with hypotrichosis syndrome, characterized by congenital ichthyosis associated with abnormal hair. Using homozygosity mapping, we mapped the disease locus to 11q24.3-q25. We screened the ST14 gene, which encodes matriptase, since transplantation of skin from matriptase(−/−)-knockout mice onto adult athymic nude mice has been shown elsewhere to result in an ichthyosislike phenotype associated with almost complete absence of erupted pelage hairs. Mutation analysis revealed a missense mutation, G827R, in the highly conserved peptidase S1–S6 domain. Marked skin hyperkeratosis due to impaired degradation of the stratum corneum corneodesmosomes was observed in the affected individuals, which suggests that matriptase plays a significant role in epidermal desquamation

Homozygous MED25 mutation implicated in eye-intellectual disability syndrome

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

SOBP Is Mutated in Syndromic and Nonsyndromic Intellectual Disability and Is Highly Expressed in the Brain Limbic System

Intellectual disability (ID) affects 1%–3% of the general population. We recently reported on a family with autosomal-recessive mental retardation with anterior maxillary protrusion and strabismus (MRAMS) syndrome. One of the reported patients with ID did not have dysmorphic features but did have temporal lobe epilepsy and psychosis. We report on the identification of a truncating mutation in the SOBP that is responsible for causing both syndromic and nonsyndromic ID in the same family. The protein encoded by the SOBP, sine oculis binding protein ortholog, is a nuclear zinc finger protein. In mice, Sobp (also known as Jxc1) is critical for patterning of the organ of Corti; one of our patients has a subclinical cochlear hearing loss but no gross cochlear abnormalities. In situ RNA expression studies in postnatal mouse brain showed strong expression in the limbic system at the time interval of active synaptogenesis. The limbic system regulates learning, memory, and affective behavior, but limbic circuitry expression of other genes mutated in ID is unusual. By comparing the protein content of the +/jc to jc/jc mice brains with the use of proteomics, we detected 24 proteins with greater than 1.5-fold differences in expression, including two interacting proteins, dynamin and pacsin1. This study shows mutated SOBP involvement in syndromic and nonsyndromic ID with psychosis in humans