Unraveling haplotype errors in the DFNA33 locus.

Genetic heterogeneity makes it difficult to identify the causal genes for hearing loss. Studies from previous decades have mapped numerous genetic loci, providing critical supporting evidence for gene discovery studies. Despite widespread sequencing accessibility, many historically mapped loci remain without a causal gene. The DFNA33 locus was mapped in 2009 and coincidentally contains ATP11A, a gene recently associated with autosomal dominant hearing loss and auditory neuropathy type 2. In a rare opportunity, we genome-sequenced a member of the original family to determine whether the DFNA33 locus may also be assigned to ATP11A. We identified a deep intronic variant in ATP11A that showed evidence of functionally normal splicing. Furthermore, we re-assessed haplotypes from the originally published DFNA33 family and identified two double recombination events and one triple recombination event in the pedigree, a highly unlikely occurrence, especially at this scale. This brief research report also serves as a call to the community to revisit families who have previously been involved in gene mapping studies, provide closure, and resolve these historical loci.

Intrafamilial phenotypic variability of Specific Language Impairment.

We investigated language functions in 32 members of a four generation family with several members affected by Specific Language Impairment with an extensive language test battery in order to determine the prevalence, overlap, and homogeneity of linguistic deficits within one pedigree. In sum, one fourth of all family members tested fulfilled the criteria of Specific Language Impairment. Despite of some similarities in language abilities, different combinations of language deficits were observed, and individual language profiles varied substantially. Thus, though there is a high prevalence of language deficits in this family which raises the likelihood of a genetic origin of these deficits, and though all affected study participants displayed selective linguistic deficits with normal non-verbal functioning, language testing showed considerable variance in overlap and homogeneity of linguistic deficits. Thus, even in one genetic population, an underlying linguistic disorder manifests itself in different language abilities to a variant degree.

CNNM2 mutations cause impaired brain development and seizures in patients with hypomagnesemia.

Intellectual disability and seizures are frequently associated with hypomagnesemia and have an important genetic component. However, to find the genetic origin of intellectual disability and seizures often remains challenging because of considerable genetic heterogeneity and clinical variability. In this study, we have identified new mutations in CNNM2 in five families suffering from mental retardation, seizures, and hypomagnesemia. For the first time, a recessive mode of inheritance of CNNM2 mutations was observed. Importantly, patients with recessive CNNM2 mutations suffer from brain malformations and severe intellectual disability. Additionally, three patients with moderate mental disability were shown to carry de novo heterozygous missense mutations in the CNNM2 gene. To elucidate the physiological role of CNNM2 and explain the pathomechanisms of disease, we studied CNNM2 function combining in vitro activity assays and the zebrafish knockdown model system. Using stable Mg(2+) isotopes, we demonstrated that CNNM2 increases cellular Mg2+ uptake in HEK293 cells and that this process occurs through regulation of the Mg(2+)-permeable cation channel TRPM7. In contrast, cells expressing mutated CNNM2 proteins did not show increased Mg(2+) uptake. Knockdown of cnnm2 isoforms in zebrafish resulted in disturbed brain development including neurodevelopmental impairments such as increased embryonic spontaneous contractions and weak touch-evoked escape behaviour, and reduced body Mg content, indicative of impaired renal Mg(2+) absorption. These phenotypes were rescued by injection of mammalian wild-type Cnnm2 cRNA, whereas mammalian mutant Cnnm2 cRNA did not improve the zebrafish knockdown phenotypes. We therefore concluded that CNNM2 is fundamental for brain development, neurological functioning and Mg(2+) homeostasis. By establishing the loss-of-function zebrafish model for CNNM2 genetic disease, we provide a unique system for testing therapeutic drugs targeting CNNM2 and for monitoring their effects on the brain and kidney phenotype.