KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome.

We describe a case of severe neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice, hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenital dyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found that human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis.

Molecular and morphological analysis of adenoid cystic carcinoma of the breast with synchronous tubular adenosis.

Adenoid cystic carcinoma (ACC) of the breast is a rare tumour. Its recognition as a special type of breast carcinoma is very important because its prognosis is better than the not-otherwise-specified invasive ductal carcinoma and its treatment may not include axillary dissection. Tubular adenosis (TA) is a very rare condition of the breast that is histologically benign; however, it has been described in association with invasive ductal carcinoma. There are scant data regarding the molecular genomic alterations in ACC of the breast and no data has been presented on TA. Herein, we provide a morphological characterisation of TA arising synchronically with ACC in the breast. To characterise these lesions, we performed ultrastructural analysis, three-dimensional reconstruction and molecular analysis using immunohistochemistry and comparative genomic hybridisation. The copy number alterations found in ACC were restricted to small deletions on 16p and 17q only, whereas the TA harboured gains on 1q, 5p, 8q, 10q, 11p and 11q and losses on 1p, 10q, 11q, 12q, 14q, 15q and 16q. These molecular data highlight the genomic instability of TA, a benign florid proliferation intermingled with ACC, and do not provide evidence of molecular evolution from TA to ACC.

More parasitic myositis cases in humans in Australia, and the definition of genetic markers for the causative agents as a basis for molecular diagnosis.

Since 1998, there have been six reported human cases of myositis in Australia, attributable to infection with the nematode Haycocknema perplexum. However, an unequivocal diagnosis of H. perplexum infection and associated disease has been seriously compromised by a lack of molecular markers for this nematode. Here, we report new cases of disseminated myositis in two male patients from the states of Queensland and Tasmania in Australia, respectively; genetically characterize the causative agent from each case; and, also establish a PCR-based sequencing approach as a tool to support the diagnosis of future cases and to underpin epidemiological studies.

Giant axonal neuropathy diagnosed on skin biopsy.

Evaluation of hereditary axonal neuropathy in childhood is complex. Often, the child has to be subjected to general anaesthesia for a nerve biopsy to guide further genetic testing, which may or may not be readily available. We describe a toddler with clinical features suggesting giant axonal neuropathy (GAN), whose diagnosis was confirmed by minimally invasive skin biopsy and corroborated by the finding of compound heterozygous mutations involving the GAN gene, including a novel interstitial microdeletion at 16q23.2 detected by microarray and a point mutation detected by direct sequencing.