Genetic and phenotypic characterization of NKX6‐2‐related spastic ataxia and hypomyelination

Abstract

Background and purposeHypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi‐allelic mutations in NKX6‐2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy.MethodsUsing a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6‐2 mutations in a multicentre setting is described. Then, all reported NKX6‐2 mutations and those identified in this study were combined and an in‐depth analysis of NKX6‐2‐related disease spectrum was provided.ResultsEleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6‐2 were identified, evidencing a high NKX6‐2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6‐2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur.ConclusionsNKX6‐2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6‐2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels.

Hematological findings associated with tubulin‐folding cofactors D‐related encephalopathy: Expanding the phenotype

“…We performed filtering steps on the WES as described previously 12,13,15‐17 . The analysis yielded a single most plausible candidate, a homozygous missense variant in TBCD (NM_005993.5: c.1712A > G, p.K571R) in family A. Sanger sequencing confirmed complete segregation of the variant within the family (Figure 1(A)).…”

SLC25A42‐associated mitochondrial encephalomyopathy: Report of additional founder cases and functional characterization of a novel deletion

“…Chip hybridization, scanning, image processing, and preliminary data analysis were all done according to manufacturers' protocols and guidelines. Autozygome analysis was performed using AutoSNPa software 9‐13 …”

“…Generated data were analyzed using publicly and commercially available tools and software. After the analysis of the WES data, the variants were filtered as previously described 9,10,12‐14 …”

“…As part of a routine workflow, we performed autozygosity mapping based on genome‐wide SNP calls to detect shared runs of homozygosity (ROHs) in the family (family 1) as well as WES in the index case. Based on established protocols, we proceeded to iterative filtering as described previously 9‐13 . The analysis yielded the previously reported, single homozygous variant in SLC25A42 (NM_178526.3:c.871A > G:p.Asn291Asp) in patient 1 6 (Figure S1).…”

Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)

“…1a). As part of routine diagnostic procedures, the DNA samples were run for WES analysis and filtered according to published protocols [4][5][6][7][8]. Then all the DNA samples were also genotyped using Genechip axiom arrays (Affymetrix Inc.) that consists more than 600,000 SNPs distributed throughout the human genome.…”