Mutations in HID1 Cause Syndromic Infantile Encephalopathy and Hypopituitarism.

OBJECTIVE: Precursors of peptide hormones undergo posttranslational modifications within the trans-Golgi network (TGN). Dysfunction of proteins involved at different steps of this process cause several complex syndromes affecting the central nervous system (CNS). We aimed to clarify the genetic cause in a group of patients characterized by hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy. METHODS: Whole exome sequencing was performed in seven individuals of six unrelated families with these features. Postmortem histopathological and HID1 expression analysis of brain tissue and pituitary gland were conducted in one patient. Functional consequences of the homozygous HID1 variant p.R433W were investigated by Seahorse XF Assay in fibroblasts of two patients. RESULTS: Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in all patients. Postmortem examination confirmed cerebral atrophy with enlarged lateral ventricles. Markedly reduced expression of pituitary hormones was found in pituitary gland tissue. Colocalization of HID1 protein with the TGN was not altered in fibroblasts of patients compared to controls, while the extracellular acidification rate upon stimulation with potassium chloride was significantly reduced in patient fibroblasts compared to controls. INTERPRETATION: Our findings indicate that mutations in HID1 cause an early infantile encephalopathy with hypopituitarism as the leading presentation, and expand the list of syndromic CNS diseases caused by interference of TGN function. ANN NEUROL 2021;90:149-164.

Hepatocyte nuclear factor-1beta gene deletions--a common cause of renal disease.

BACKGROUND: Hepatocyte nuclear factor-1beta (HNF-1beta) is a critical transcription factor in pancreatic and renal development. Our previous report identified HNF-1beta mutations in 23/160 patients with unexplained renal disease. The most common phenotype is renal cysts, which is frequently associated with early-onset diabetes in the renal cysts and diabetes (RCAD) syndrome. HNF-1beta gene deletions have recently been shown to cause renal malformations and early-onset diabetes. METHODS: We developed a multiplex ligation-dependent probe amplification (MLPA) assay for HNF-1beta gene dosage analysis and tested patients with unexplained renal disease in whom mutations had not been found by sequencing. RESULTS: Whole HNF-1beta gene deletions were detected in 15/133 probands. Renal cysts were present in 13/15, including three with glomerulocystic kidney disease and one with cystic renal dysplasia. Renal function ranged from normal to transplantation aged 3 years. Ten probands had diabetes (nine having RCAD). In addition, four had abnormal liver function tests, two showed pancreatic atrophy and 3/10 female probands had uterine malformations. Whole HNF-1beta gene deletions are a common cause of developmental renal disease, particularly renal cystic disease with or without diabetes. CONCLUSIONS: The phenotype associated with deletions or coding region/splicing mutations is very similar suggesting that haploinsufficiency is the underlying mechanism. Patients with features suggestive of the HNF-1beta clinical phenotype should be tested for mutations both by sequence and dosage analysis.