Prenatal phenotype of PNKP-related primary microcephaly associated with variants affecting both the FHA and phosphatase domain.

Biallelic PNKP variants cause heterogeneous disorders ranging from neurodevelopmental disorder with microcephaly/seizures to adult-onset Charcot-Marie-Tooth disease. To date, only postnatal descriptions exist. We present the first prenatal diagnosis of PNKP-related primary microcephaly. Pathological examination of a male fetus in the 18th gestational week revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities. Prenatal trio-exome sequencing identified compound heterozygosity for the PNKP variants c.498G>A, p.[(=),0?] and c.302C>T, p.(Pro101Leu). Segregation confirmed both variants in the sister fetus. Through RNA analyses, we characterized exon 4 skipping affecting the PNKP forkhead-associated (FHA) and phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the paternal c.498G>A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic PNKP-variants to compare prenatal/postnatal phenotypes. Both carry the splice donor variant c.1029+2T>C in trans with a variant in the FHA domain (c.311T>C, p.(Leu104Pro); c.151G>C, p.(Val51Leu)). RNA-seq showed complex splicing for c.1029+2T>C and c.151G>C. Structural modeling revealed significant clustering of missense variants in the FHA domain with variants generating structural damage. Our clinical description extends the PNKP-continuum to the prenatal stage. Investigating possible PNKP-variant effects using RNA and structural modeling, we highlight the mutational complexity and exemplify a PNKP-variant characterization framework.

Spastin related hereditary spastic paraplegia with dysplastic corpus callosum.

Thin corpus callosum has been recently observed in two patients with an autosomal dominant trait of hereditary spastic paraplegia (HSP) linked to a novel mutation in the spastin gene (SPG4). In the same two patients cerebellar atrophy has been found. Reportedly, in other members of the same family, there has been a variable presence of mental retardation. We report on the clinical and genetic investigation of an Austrian family with a novel mutation in the spastin gene. Genetic analysis of the SPG4 locus revealed a mutation (C1120A) and a known intronic polymorphism (996-47G>A) of the spastin gene. In one affected family member, previously undescribed dysplasia of the corpus callosum (CC) was found in conjunction with otherwise uncomplicated HSP. Dysplastic CC was not paralleled with cortical atrophy, cognitive impairment or other phenotypic variations. Two further affected family members showed the same mutation and polymorphism, but no evidence of CC abnormalities. We conclude that apparently pure HSP may present with MRI features of dysplastic CC. This finding extended the spastin-related phenotype which is distinct from previous reports of thin CC in HSP.

Decreasing uptake of predictive testing for Huntington's disease in a German centre: 12 years' experience (1993-2004).

In this retrospective study, we examined changes in decision-making for and against the predictive genetic test for Huntington's disease including 478 persons at risk who had undergone genetic counselling in one centre in Germany between 1993 and 2004. At the outset of the counselling procedure the majority of subjects (71%) wanted to make use of the test, yet the actual demand of the predictive test result declined from 67 to 38% over the years. In addition, the time interval between counselling session and blood withdrawal was reduced, as determined by the counselees: in 2000-2004 the majority of persons at risk made the appointment for blood withdrawal after the shortest possible time span. Demographic factors of the cohort remained comparatively stable in the investigated time period. An association was evident between the ratio of test usage and the counselling person. These and other possible factors influencing the time flow of predictive DNA testing are discussed. Further studies are necessary to investigate whether changes of test demand rates are a general phenomenon.