Holoprosencephaly 12 With Or Without Pancreatic Agenesis

A number sign (#) is used with this entry because of evidence that holoprosencephaly-12 with or without pancreatic agenesis (HPE12) is caused by heterozygous mutation in the CNOT1 gene (604917) on chromosome 16q21.

Description

Holoprosencephaly-12 with or without pancreatic agenesis (HPE12) is a developmental disorder characterized by abnormal separation of the embryonic forebrain (HPE) resulting in dysmorphic facial features and often, but not always, impaired neurologic development. Most patients with this form of HPE also have congenital absence of the pancreas, resulting in early-onset insulin-dependent diabetes mellitus and requiring pancreatic enzyme replacement. Other features may include hearing loss and absence of the gallbladder (summary by De Franco et al., 2019 and Kruszka et al., 2019).

For a phenotypic description and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100).

Clinical Features

De Franco et al. (2019) reported 3 unrelated patients with variable features suggestive of holoprosencephaly who were brought to attention due to congenital pancreatic agenesis. The patients developed insulin-dependent diabetes mellitus in the first days or weeks of life, as well as pancreatic exocrine deficiency requiring enzyme supplementation. Two patients had intrauterine growth retardation (IUGR) and absence of the gallbladder. Brain imaging of 2 patients showed lobar holoprosencephaly, dysplastic frontal horns of the lateral ventricles, missing septum pellucidum, and/or agenesis or hypoplasia of the corpus callosum. One (patient P01) had muscle weakness, low-set ears, onset of complex focal seizures at age 3, and mild learning difficulties at age 9 years. The second patient (P02), previously reported by Hilbrands et al. (2017), died at age 12 weeks. She was noted to have dysmorphic features, including receding forehead, cylindrical nose, mild hypotelorism, dysplastic left ears, hypoplastic zygomatic arch, and adducted thumbs. The third patient (P03) was a 16-year-old boy who attended a normal school and had no developmental concerns. He had mild dysmorphic features, including prominent occiput, low-set ears, high-arched palate, and prominent incisors suggestive of HPE, but brain imaging was not performed.

Kruszka et al. (2019) reported 2 unrelated patients with HPE. The first patient was born at 33 weeks' gestation after a pregnancy complicated by IUGR. He had pancreatic insufficiency with insulin-dependent diabetes mellitus and exocrine deficiency necessitating enzyme therapy, as well as diabetes insipidus. The second patient did not have IUGR or pancreatic insufficiency. Dysmorphic features common to both children included microcephaly, hypotelorism, epicanthal folds, long philtrum, and depressed nasal bridge; 1 had microtia. Other features included global developmental delay, hypotonia or spasticity, inability to walk, and conductive and/or sensorineural hearing loss. Patient 1 died at age 16 months. Brain imaging showed semilobar HPE in both patients.

Molecular Genetics

In 3 unrelated patients with HPE12, De Franco et al. (2019) identified a de novo heterozygous missense mutation in the CNOT1 gene (R535C; 604917.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in available parental DNA samples. Functional studies of the variant and studies of patient cells were not performed, but generation of the mutation in mice resulted in abnormalities similar to those seen in the patients (see ANIMAL MODEL).

In 2 unrelated patients with HPE12, Kruszka et al. (2019) identified a heterozygous de novo R535C mutation. The mutation was found by exome sequencing and confirmed by Sanger sequencing; the patients were ascertained from a cohort of 134 parent-child trios with HPE who underwent whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed. In situ hybridization studies on mouse embryos at gestation day 8.25 showed expression of Cnot1 in both the neuroectoderm and mesenchyme of the neural folds during primary neurulation. The findings confirmed that this gene is expressed during the critical period for forebrain division, thus providing evidence for its role in the disorder.

Animal Model

De Franco et al. (2019) generated a mouse line carrying the R535C mutation in CNOT1. Heterozygous mice were born at a lower than expected frequency, but did not have an obvious phenotype, whereas homozygosity for the mutation was embryonic lethal. Analysis of E14.5 homozygous mutant embryos showed a small pancreas, exencephaly, eye defects (mostly coloboma), and edema. These abnormalities were associated with changes in gene expression in pancreatic tissue, including an increase in Shh (600725) and a decrease in Pdx1 (600733), Hnf1B (189907), and Ptf1A (607194), all of which are believed to play a role in pancreatic development.