The Hox genes are an evolutionarily conserved family of genes, which encode a class of important transcription factors that function in numerous developmental processes. Following their initial discovery, a substantial amount of information has been gained regarding the roles Hox genes play in various physiologic and pathologic processes. These processes range from a central role in anterior-posterior patterning of the developing embryo to roles in oncogenesis that are yet to be fully elucidated. In vertebrates there are a total of 39 Hox genes divided into 4 separate clusters. Of these, mutations in 10 Hox genes have been found to cause human disorders with significant variation in their inheritance patterns, penetrance, expressivity and mechanism of pathogenesis. This review aims to describe the various phenotypes caused by germline mutation in these 10 Hox genes that cause a human phenotype, with specific emphasis paid to the genotypic and phenotypic differences between allelic disorders. As clinical whole exome and genome sequencing is increasingly utilized in the future, we predict that additional Hox gene mutations will likely be identified to cause distinct human phenotypes. As the known human phenotypes closely resemble gene-specific murine models, we also review the homozygous loss-of-function mouse phenotypes for the 29 Hox genes without a known human disease. This review will aid clinicians in identifying and caring for patients affected with a known Hox gene disorder and help recognize the potential for novel mutations in patients with phenotypes informed by mouse knockout studies.

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo NG ET AL. | 909

No abstract

We present the biochemical and molecular diagnosis of dihydrolipoamide dehydrogenase (DLD) deficiency (also known as E3 deficiency) and Leigh syndrome in a 14 year-old girl with previous history of learning disability and episodic encephalopathy and ketoacidosis. The diagnosis was suggested by biochemical laboratory values from plasma amino acids and urine organic acids, which were obtained during an acute episode of encephalopathy, lactic ketoacidosis and liver failure all precipitated by infectious mononucleosis. DLD deficiency was confirmed via enzymatic and molecular analyses. E3 activity from cultured skin fibroblasts ranged between 9% and 29% of the mean. Molecular analysis showed compound heterozygosity for novel and previously reported pathogenic mutations; p.I353T and p.G136del, respectively. The patient was managed using a combination of dietary augmentation as well as continuous renal replacement therapy given her severe and persistent lactic acidosis. Her acute decompensation resulted in brain MRI changes involving the posterior aspect of the putamina, lateral and medial thalami, substantia nigra, lateral geniculate bodies and splenium of the corpus callosum. Additional affected regions included the cortex and subcortical white matter of the right and left occipital lobes and the peri-rolandic region. We review the literature of molecularly confirmed patients with DLD deficiency and note that Leigh syndrome is common in reported patients. This case provides further evidence of the heterogeneous presentation of DLD deficiency as our patient presented with her most severe decompensation at an age much more advanced than in previously reported patients.

Melanomas are associated with several hereditary conditions. We present a large family with several family members affected with primary melanomas and dysplastic nevi as well as thyroid cancer and other malignant tumors. Clinical work-up did not reveal a mutation in any of the genes usually considered with evaluation for predisposition to melanoma (BRCA1/2, CDKN2A, CDK4, PTEN, TP53). Whole exome sequencing of five affected family members showed a new variant in POT1. POT1 is associated with the telomere shelterin complex that regulates telomere protection and telomerase access. Germline mutations in POT1 were recently shown to be associated with hereditary predisposition to melanoma. Our findings support a role of POT1 germline mutations in cancer predisposition beyond melanoma development, suggesting a broader phenotype of the POT1-associated tumor predisposition syndrome that might also include thyroid cancer as well as possibly other malignant tumors.