Grandparental genotyping enhances exome variant interpretation.

Trio exome sequencing is a powerful tool in the molecular investigation of monogenic disorders and provides an incremental diagnostic yield over proband-only sequencing, mainly due to the rapid identification of de novo disease-causing variants. However, heterozygous variants inherited from unaffected parents may be inadvertently dismissed, although multiple explanations are available for such scenarios including mosaicism in the parent, incomplete penetrance, imprinting, or skewed X-inactivation. We report three probands, in which a pathogenic or likely pathogenic variant was identified upon exome sequencing, yet was inherited from an unaffected parent.

An Ashkenazi Jewish founder mutation in causes retinal phenotype in both hemizygous males and heterozygous female carriers.

: Mutations in have been mainly associated with X-linked incomplete congenital stationary night blindness (icCSNB). Variable phenotypic expression in females was reported in some families. We report here three non-related Ashkenazi Jewish families originating in Eastern Europe, that included males and a many affected females, initially diagnosed with variable retinal phenotypes.

Complex chromosomal rearrangement in a girl with psychomotor-retardation and a de novo inversion: inv(2)(p15;q24.2).

Cytogenetic analysis of DNA from a girl with severe psychomotor retardation revealed a de novo pericentric inversion of chromosome 2: 46,XX,inv(2)(p15q24.2). In order to elucidate the possible role of the inversion in the girl's abnormal phenotype, we analyzed the inversion breakpoints.

A non-ancestral RPGR missense mutation in families with either recessive or semi-dominant X-linked retinitis pigmentosa.

Most X-linked diseases show a recessive pattern of inheritance in which female carriers are unaffected. In X-linked retinitis pigmentosa (XLRP), however, both recessive and semi-dominant inheritance patterns have been reported. We identified an Israeli family with semi-dominant XLRP due to a missense mutation (p.

Hereditary spastic paraplegia with thin corpus callosum: reduction of the SPG11 interval and evidence for further genetic heterogeneity.

Background: Hereditary spastic paraplegia (HSP) with thin corpus callosum (TCC) is an autosomal recessive form of complicated HSP mainly characterized by slowly progressive spastic paraparesis and mental deterioration beginning in the second decade of life. The locus for HSP-TCC, designated SPG11, was mapped to chromosome 15q13-15 in some of the affected families from Japan, Europe, and North America, spanning an interval of 17.5 megabases (Mb).

A patient with Prader-Willi syndrome and a supernumerary marker chromosome r(15)(q11.1-13p11.1)pat and maternal heterodisomy.

We report on a Prader-Willi patient with a de novo supernumerary marker chromosome (SMC) in 16% of the cells. The SMC was a ring chromosome and it included the PWS/AS critical region as was demonstrated by FISH. Segregation analysis indicated that the SMC originated from a paternal chromosome 15 and the two normal chromosomes 15 of the patients were of the maternal homologues.

Prevalence of myotonic dystrophy in Israeli Jewish communities: inter-community variation and founder premutations.

In a comprehensive epidemiological survey among Jews living in Israel, the average prevalence of myotonic dystrophy (DM) was 15.7/10(5) (1 case in 6369) with intercommunity variations; the Ashkenazi Jews had the lowest rate, 5.7/10(5) (1 case in 17544) as compared to the rate in the Sephardim/Oriental Jews 20/10(5) (1 case in 5000) and the in the Yemenite Jews 47.

Uniparental disomy in fetuses diagnosed with balanced Robertsonian translocations: risk estimate.

Forty-two fetuses with non-homologous Robertsonian translocations were analyzed for uniparental disomy (UPD). One fetus with a de novo translocation t(13q;14q) had maternal isodisomy of chromosome 14. In a summary of the published data (including the present study), 315 cases were analyzed for UPD after prenatal diagnosis of balanced Robertsonian translocations, of these two fetuses had UPD, giving a risk estimate of 0.