Elizabeth Ives

Linkage analysis of 26 Canadian breast and breast-ovarian cancer families.

We have examined 26 Canadian families with hereditary breast or ovarian cancer for linkage to markers flanking the BRCA1 gene on chromosome 17q12–q21. Of the 15 families that contain cases of ovarian cancer, 94% were estimated to be linked to BRCA1. In contrast, there was no overall evidence of linkage in the group of 10 families with breast cancer without ovarian cancer. A genetic recombinant in a breast-ovarian cancer family indicates a placement of BRCA1 telomeric to D17S776, and helps to define the region of assignment of the cancer susceptibility gene. Other cancers of interest that appeared in the BRCA1-linked families included primary peritoneal cancer, cancer of the fallopian tube, and malignant melanoma.

A Locus for Autosomal Dominant Hereditary Spastic Ataxia, SAX1,Maps to Chromosome 12p13

The hereditary spastic ataxias (HSA) are a group of clinically heterogeneous neurodegenerative disorders characterized by lower-limb spasticity and generalized ataxia. HSA was diagnosed in three unrelated autosomal dominant families from Newfoundland, who presented mainly with severe leg spasticity, dysarthria, dysphagia, and ocular-movement abnormalities. A genomewide scan was performed on one family, and linkage to a novel locus for HSA on chromosome 12p13, which contains the as-yet-unidentified gene locus SAX1, was identified. Fine mapping confirmed linkage in the two large families, and the third, smaller family showed LOD scores suggestive of linkage. Haplotype construction by use of 13 polymorphic markers revealed that all three families share a disease haplotype, which key recombinants and overlapping haplotypes refine to about 5 cM, flanked by markers D12S93 and GATA151H05. SAX1 is the first locus mapped for autosomal dominant HSA.

Characterization of a new full length TMPRSS3 isoform and identification of mutant alleles responsible for nonsyndromic recessive deafness in Newfoundland and Pakistan

BackgroundMutant alleles of TMPRSS3 are associated with nonsyndromic recessive deafness (DFNB8/B10). TMPRSS3 encodes a predicted secreted serine protease, although the deduced amino acid sequence has no signal peptide. In this study, we searched for mutant alleles of TMPRSS3 in families from Pakistan and Newfoundland with recessive deafness co-segregating with DFNB8/B10 linked haplotypes and also more thoroughly characterized the genomic structure of TMPRSS3.MethodsWe enrolled families segregating recessive hearing loss from Pakistan and Newfoundland. Microsatellite markers flanking the TMPRSS3 locus were used for linkage analysis. DNA samples from participating individuals were sequenced for TMPRSS3. The structure of TMPRSS3 was characterized bioinformatically and experimentally by sequencing novel cDNA clones of TMPRSS3.ResultsWe identified mutations in TMPRSS3 in four Pakistani families with recessive, nonsyndromic congenital deafness. We also identified two recessive mutations, one of which is novel, of TMPRSS3 segregating in a six-generation extended family from Newfoundland. The spectrum of TMPRSS3 mutations is reviewed in the context of a genotype-phenotype correlation. Our study also revealed a longer isoform of TMPRSS3 with a hitherto unidentified exon encoding a signal peptide, which is expressed in several tissues.ConclusionMutations of TMPRSS3 contribute to hearing loss in many communities worldwide and account for 1.8% (8 of 449) of Pakistani families segregating congenital deafness as an autosomal recessive trait. The newly identified TMPRSS3 isoform e will be helpful in the functional characterization of the full length protein.

Profound, prelingual nonsyndromic deafness maps to chromosome 10q21 and is caused by a novel missense mutation in the Usher syndrome type IF gene PCDH15.

We studied a consanguineous family (Family A) from the island of Newfoundland with an autosomal recessive form of prelingual, profound, nonsyndromic sensorineural hearing loss. A genome-wide scan mapped the deafness trait to 10q21-22 (max LOD score of 4.0; D10S196) and fine mapping revealed a 16 Mb ancestral haplotype in deaf relatives. The PCDH15 gene was mapped within the critical region and was an interesting candidate because truncating mutations cause Usher syndrome type IF (USH1F) and two missense mutations have been previously associated with isolated deafness (DFNB23). Sequencing of the PCDH15 gene revealed 33 sequencing variants. Three of these variants were homozygous exclusively in deaf siblings but only one of them was not seen in ethnically matched controls. This novel c.1583 T>A transversion predicts an amino-acid substitution of a valine with an aspartic acid at codon 528 (V528D). Like the two DFNB23 mutations, the V528D mutation in Family A occurs in a highly conserved extracellular cadherin (EC) domain of PCDH15 and is predicted to be more deleterious than the previously identified DFNB23 missense mutations (R134G and G262D). Physical assessment, vestibular and visual function testing in deaf adults ruled out syndromic deafness because of Usher syndrome. This study validates the DFNB23 designation and supports the hypothesis that missense mutations in conserved motifs of PCDH15 cause nonsyndromic hearing loss. This emerging genotype–phenotype correlation in USH1F is similar to that in several other USH1 genes and cautions against a prognosis of a dual sensory loss in deaf children found to be homozygous for hypomorphic mutations at the USH1F locus.

Regional localization of an X-linked mental retardation gene to Xp21.1-Xp22.13 (MRX38)

A gene responsible for X-linked mental retardation with macrocephaly and seizures (MRX38) in a family with five affected males in three generations was localized to Xp21.1-p22.13 by linkage analysis. Recombination events placed the gene between DXS1226 distally and DXS1238 proximally, defining an interval of approximately 14 cM. A peak lod score of 2.71 was found with several loci in Xp21.1 (DXS992, DXS1236, DXS997, and DXS1036) at a recombination fraction of zero. The map intervals of 5 X-linked mental retardation loci, MRX2 (Xp22.1-p22.2), MRX19 (Xp22), MRX21 (Xp21.1-p22.3), MRX29 (Xp21.2-p22.1), and MRX32 (Xp21.2-p22.1), and two syndromal mental retardation loci, Partington syndrome (PRTS; Xp22) and Coffin-Lowry syndrome (CLS; Xp22.13-p22.2), overlap this region. As none of these display the same phenotype seen in the family reported here, this X-linked mental retardation locus may represent a new entity.

A founder effect in three large Newfoundland families with a novel clinically variable spastic ataxia and supranuclear gaze palsy

A distinctive slowly progressive neurodegenerative disorder, which falls under a new category of neurological diseases, the hereditary spastic ataxias (HSA), is described in three independently ascertained Newfoundland kindreds. HSA is a heterogeneous group of disorders in which pyramidal tract features overlap cerebellar characteristics. The families are assumed to have the same condition as, although apparently unrelated, all originate in a historically isolated cluster of rural communities and link to the same locus at 12p13, SAX1. Clinically the phenotype is very variable but lower limb hypertonicity and hyperreflexia are early and prominent generally preceded by eye movement abnormality, an impaired vertical downward saccade and a typical involuntary head jerk. These are followed by variable levels of ataxia, dysarthria, and dysphagia. Onset occurs in the first two decades and can be detected in most by early adulthood. Significant mobility problems are present by the fourth decade with a broad based ataxic and spastic gait. MRI scans of brain and spinal cord were normal. Neuropathology showed degeneration of corticospinal tracts and posterior columns and midbrain neuronal loss. The phenotype is striking in its diversity among and within families and the variability of expression can be observed within the same sibship. Pedigree analysis shows no evidence of anticipation or any sex differences in severity. The condition is unusually prevalent in the province of Newfoundland, which is characteristic of a founder effect followed by isolation and large family size. Fine mapping efforts have reduced the critical interval of the SAX1 locus to 1.9Mb. Identification of the SAX1 gene will help to clarify the pathogenesis of this type of HSA.

833 EVALUATION OF GENETIC COUNSELING FOLLOWING THE BIRTH OF A MALFORMED NEWBORN

The benefits of routine genetic counseling (GC) in ameliorating the family impact of a malformed newborn were investigated by a comparison of 2 Saskatchewan cities Saskatoon (S) and Regina (R). During 33 months all newborns in S and R having a significant malformation were ascertained. (S 122, R 130). A questionnaire (Q), State Trait Anxiety Inventory (STAI) and Family Unit Inventory (FUI) were administered at home to parents of both groups 6 weeks following the birth (T1). S parents only were offered GC which 112 accepted. STAI and FUI were administered again to S and R parents at 6 months (T2), and 1 year (T3). 110 S and 112 R parents were followed to T3. The malformation groups were, with minor exceptions, comparable S v. R. Group comparison of all other variables individually revealed no significant differences S v. R. The impression that GC conferred no particular benefit to families was therefore further explored by development of a family vulnerability index derived by grouping scores from different combinations of variables. Similarly vulnerable S and R families were compared for change in parental anxiety and FUI scores and knowledge of both reproductive risks and the childs condition. Factors influencing response to GC include survival v. demise of the infant, more severe malformation, availability of prenatal diagnosis, lower parental education and income, single mother, parental age difference and certain FUI characteristics. Identification of situations where GC adds significantly to regular management may permit a more appropriate allocation of this limited resource.