Spondylo-epiphyseal dysplasia in two sibs due to a homozygous splicing variant in COL2A1.

Type 2 collagenopathies encompass a large group of chondrodysplasias ranging from the perinatally lethal achondrogenesis type 2 and hypochondrogenesis at the severe end of the spectrum to early-onset osteoarthritis with normal stature at the milder end of the spectrum. With the exception of a few reported cases, these dysplasias are predominantly caused by heterozygous variants in the COL2A1 gene and hence show an autosomal dominant inheritance pattern. Here we report on two siblings, originating from a consanguineous family, who presented with disproportionate short stature, ocular abnormalities, cleft palate and hearing impairment. The radiographic study showed signs of a spondyloepiphyseal dysplasia, compatible with a type 2 collagen disorder. Indeed, both siblings were homozygous for a c.3111+2T > Cp.(Glu1033Lysfs*5) splice site variant in the COL2A1 gene. cDNA analysis performed on skin fibroblasts from the affected sibs revealed the co-occurrence of the wild-type transcript and an aberrant splice product, the latter believed to be degraded by nonsense-mediated mRNA decay. The parents who were heterozygous for this variant were phenotypically normal. This paper confirms that type 2 collagenopathies can show an autosomal recessive inheritance.

A founder nonsense variant in NUDT2 causes a recessive neurodevelopmental disorder in Saudi Arab children.

We identified the homozygous p.Arg12* variant in 5 patients with neurodevelopmental delay, but variation databases list many truncating heterozygous variants for this small 2-exon gene. As most of these affect the protein's C-terminus, loss-of-function mediated pathogenicity may be confined to bi-allelic truncating variants in exon 1 (nonsense-mediated decay!) or in the catalytically active Nudix box.

Expanding the clinical and genetic spectra of NKX6-2-related disorder.

Hypomyelinating leukodystrophies (HLDs) affect the white matter of the central nervous system and manifest as neurological disorders. They are genetically heterogeneous. Very recently, biallelic variants in NKX6-2 have been suggested to cause a novel form of autosomal recessive HLD. Using whole-exome or whole-genome sequencing, we identified the previously reported c.196delC and c.487C>G variants in NKX6-2 in 3 and 2 unrelated index cases, respectively; the novel c.608G>A variant was identified in a sixth patient. All variants were homozygous in affected family members only. Our patients share a primary diagnosis of psychomotor delay, and they show spastic quadriparesis, nystagmus and hypotonia. Seizures and dysmorphic features (observed in 2 families each) represent an addition to the phenotype, while developmental regression (observed in 3 families) appears to be a notable and previously underestimated clinical feature. Our findings extend the clinical and mutational spectra associated with this novel form of HLD. Comparative analysis of our 10 patients and the 15 reported previously did, however, not reveal clear evidence for a genotype-phenotype correlation.

L-2-hydroxyglutaric aciduria: identification of ten novel mutations in the L2HGDH gene.

L-2-hydroxyglutaric aciduria (L-2-HGA) is a metabolic disease with an autosomal recessive mode of inheritance. It was first reported in 1980. Patients with this disease have mutations in both alleles of the L2HDGH gene. The clinical presentation of individuals with L-2-HGA is somewhat variable, but affected individuals typically suffer from progressive neurodegeneration. Analysis of urinary organic acids reveals an increased signal of 2-hydroxyglutaric acid, mainly as the L-enantiomer. L-2-HGA is known to occur in individuals of various ethnic backgrounds, but up to now mutation analysis has been mainly focused on patients of Turkish and Portuguese origin. This led us to confirm the diagnosis on the DNA level and undertake the corresponding mutation analysis in individuals of diverse ethnicity previously diagnosed with L-2-HGA on the basis of urinary metabolites and clinical/neuroimaging data. In 24 individuals from 17 families with diverse ethnic and geographic origins, 13 different mutations were found, 10 of which have not been reported previously. At least eight of the patients were compound heterozygotes. The identification of two mutations (c.751C > T and c.905C > T in exon 7) in patients with different origins supports the view that they occurred independently in different families. In contrast, the mutation c.788C > T was detected in all six Venezuelan patients originating from the same Caribbean island of Margarita, but not in other patients, thus rendering a founder effect likely. None of the mutations was found in the control population, indicating that they are most probably causative. Mutation analysis may improve the quality of diagnosis and prenatal diagnosis of L-2-HGA.

Trigonomicrocephaly, severe micrognathia, large ears, atrioventricular septal defect, symmetrical cutaneous syndactyly of hands and feet, and multiple café-au-lait spots: new acrocraniofacial dysostosis syndrome?

We report on a patient with a unique constellation of anomalies comprising trigonomicrocephaly, asymmetric severe micrognathia, large ears, atrioventricular septal defect, vertebral anomalies, bilateral cutaneous syndactyly of fingers and toes, unilateral cryptorchidism and multiple café-au-lait spots. The mother of the propositus has multiple café-au-lait spots. Search of POSSUM and the London Dysmorphology Database (LDDB) uncovered no similar case. We think that this patient represents a new acrocraniofacial dysostosis syndrome.