Edition of 10 May 2021

A new study published in the European Journal of Medical Genetics identified a family in which four consecutive pregnancies were characterized by the combination of fetal congenital heart malformations and vertebral anomalies. Preaxial polydactyly was detected in one of the fetuses. Reanalysis of the non-diagnostic clinical exome data revealed compound heterozygous variants in ETV2, which have previously not been known to be associated with a phenotype in humans.

A new study published in the American Journal of Human Genetics identified bi-allelic pathogenic variants in HS2ST1 in four individuals from three unrelated families. Affected individuals showed facial dysmorphism with coarse face, upslanted palpebral fissures, broad nasal tip, and wide mouth, developmental delay and/or intellectual disability, corpus callosum agenesis or hypoplasia, flexion contractures, brachydactyly of hands and feet with broad fingertips and toes, and uni- or bilateral renal agenesis in three individuals. This study revealed that HS2ST1 variants cause a reduction in HS2ST1 mRNA and decreased or absent heparan sulfate 2-O-sulfotransferase 1 in two of three fibroblast cell lines derived from affected individuals. This study showed that that a heparan sulfate synthesis deficit caused a recognizable syndrome and emphasized a role for 2-O-sulfated heparan sulfate in human neuronal, skeletal, and renal development.

A new study published in Brain identified six different truncating variants in VWA1 in 15 affected individuals from six families with proximal and distal muscle weakness predominantly of the lower limbs in childhood or adulthood. This study revealed that VWA1 was a new disease gene implicated in this autosomal recessive neuromyopathic condition presenting with child-/adult-onset muscle weakness as a key clinical feature.

A new study published in Genetics in Medicine identified 13 individuals with heterozygous variants in the two human B-type lamins, LMNB1 and LMNB2. This study showed that dominant pathogenic variants in LMNB1 and LMNB2 were a genetic cause of primary microcephaly, implicating a major structural component of the nuclear envelope in its etiology and defining a new form of laminopathy

A new study published in the American Journal of Human Genetics identified a proband with focal segmental glomerulosclerosis, steroid-resistant nephrotic syndrome, developmental delay, and epilepsy with a nonsense de novo variants in TRIM8. This study revealed that truncating TRIM8 de novo variants cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in focal segmental glomerulosclerosis and developmental brain disease.