Chromosome 20p11.2 deletions cause congenital hyperinsulinism via the loss of FOXA2 or its regulatory elements.

Persistent congenital hyperinsulinism (HI) is a rare genetically heterogeneous condition characterised by dysregulated insulin secretion leading to life-threatening hypoglycaemia. For up to 50% of affected individuals screening of the known HI genes does not identify a disease-causing variant. Large deletions have previously been used to identify novel regulatory regions causing HI. Here, we used genome sequencing to search for novel large (>1 Mb) deletions in 180 probands with HI of unknown cause and replicated our findings in a large cohort of 883 genetically unsolved individuals with HI using off-target copy number variant calling from targeted gene panels. We identified overlapping heterozygous deletions in five individuals (range 3-8 Mb) spanning chromosome 20p11.2. The pancreatic beta-cell transcription factor gene, FOXA2, a known cause of HI was deleted in two of the five individuals. In the remaining three, we found a minimal deleted region of 2.4 Mb adjacent to FOXA2 that encompasses multiple non-coding regulatory elements that are in conformational contact with FOXA2. Our data suggests that the deletions in these three children may cause disease through the dysregulation of FOXA2 expression. These findings provide new insights into the regulation of FOXA2 in the beta-cell and confirm an aetiological role for chromosome 20p11.2 deletions in syndromic HI.

Parents' perspectives on the use of children's facial images for research and diagnosis: a survey.

Computer-aided facial diagnostic tools are valuable emerging technologies for the early detection and initial diagnosis of congenital disorders. These tools require large datasets of facial photographs, especially of infants and children, to identify these disorders and improve classification accuracies. Researchers need to balance this need for larger datasets with patients' privacy rights, needs and preferences. This study aimed to investigate parents' views regarding the collection, storage, use and publication of their children's facial images for research and diagnostic purposes. A total of 151 parents of children with and without congenital disorders completed an online survey evaluating their views on the collection, storage, use and publication of children's facial images for research and diagnosis. Overall, 72.5% of parents would allow researchers to take facial photographs of their children, preferring the images to be stored in a secure database that is not available to the public. Parents of children with congenital disorders were more accepting of researchers taking facial photographs of their children, compared to parents of children without these conditions. Half of the respondents would allow facial photographs of their children to be published in academic journals, without their eyes covered, and this acceptance increased as the proportion of the child's face covered increased. Parents also indicated specific requirements to allow the use of these images in other similar research studies which need to be taken into consideration when planning studies that involve facial analysis research.

A de novo 2.2 Mb recurrent 17q23.1q23.2 deletion unmasks novel putative regulatory non-coding SNVs associated with lethal lung hypoplasia and pulmonary hypertension: a case report.

BACKGROUND: Application of whole genome sequencing (WGS) enables identification of non-coding variants that play a phenotype-modifying role and are undetectable by exome sequencing. Recently, non-coding regulatory single nucleotide variants (SNVs) have been reported in patients with lethal lung developmental disorders (LLDDs) or congenital scoliosis with recurrent copy-number variant (CNV) deletions at 17q23.1q23.2 or 16p11.2, respectively. CASE PRESENTATION: Here, we report a deceased newborn with pulmonary hypertension and pulmonary interstitial emphysema with features suggestive of pulmonary hypoplasia, resulting in respiratory failure and neonatal death soon after birth. Using the array comparative genomic hybridization and WGS, two heterozygous recurrent CNV deletions: ~ 2.2 Mb on 17q23.1q23.2, involving TBX4, and ~ 600 kb on 16p11.2, involving TBX6, that both arose de novo on maternal chromosomes were identified. In the predicted lung-specific enhancer upstream to TBX4, we have detected seven novel putative regulatory non-coding SNVs that were absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. CONCLUSIONS: Our findings further support a recently reported model of complex compound inheritance of LLDD in which both non-coding and coding heterozygous TBX4 variants contribute to the lung phenotype. In addition, this is the first report of a patient with combined de novo heterozygous recurrent 17q23.1q23.2 and 16p11.2 CNV deletions.

Holoprosencephaly with Clefts: Data of 85 Patients, Treatment and Outcome: Part 1: History, Subdivisions, and Data on 85 Holoprosencephalic Cleft Patients.

CONTEXT: Cleft patients with Holoprosencephaly (HPE) constitute a controversy due to a variable facial appearance. HPE appearance varies from only a columella to a prolabium-premaxilla complex agenesis up to a common unilateral or bilateral cleft lip and palate with a single central incisor, various brain deformities, and/or even normal brain development. It is challenging to designate such various appearances, to understand their etiopathogenesis, and to choose the most appropriate management. Literature was reviewed for diagnostic criteria, pregnancy history, clinical findings, brain development, survival rate, initial perioperative management, and postsurgical midfacial growth in cleft patients with HPE. The findings were compared with a clinical database of 85 cleft patients with HPE at the Department of Maxillofacial and Oral Surgery, University of Pretoria. AIMS OF PART 1: The aim of the study is to overcome disparities widely existing among clinicians regarding definitive diagnostic criteria, especially in cases with a common appearance of a uni- or bilateral cleft lip alveolus or cleft lip, alveolus and palate deformity, and cases presenting facial structural agenesis. MATERIALS AND METHODS: A literature search related to diagnostic criteria was compared to results of a cleft HPE database from a single tertiary institution. RESULTS: HPE cleft cases can be allocated to one of the following subdivisions: (1) columella complex agenesis (Ag-Colum), (2) prolabium-premaxilla-columella complex agenesis in cleft lip-alveolus deformities (Ag-CLA), (3) prolabium-premaxilla-columella agenesis in cases with complete cleft lip alveolus palate (Ag-CLAP), and (4) standard type (holoprosencephaly in patients with a standard cleft) with uni- or bilateral CLA or CLAP, hard and soft palate cleft (hPsP), and atrophic premaxillae, with or without single central incisor. Further, incidence, variation in brain development, and appearances in HPE cleft patients of different races and gender, epilepsy, and early death are discussed. Conclusion: This paper adds new data and facts to the existing literature related to cleft lip and palate patients suffering from HPE.

A South African family with oculopharyngeal muscular dystrophy: Clinical and molecular genetic characteristics.

Autosomal dominantly inherited oculopharyngeal muscular dystrophy (OPMD) is caused by a trinucleotide repeat expansion in exon 1 of the polyadenylate binding protein nuclear 1 (PABPN1) gene on chromosome 14q. A large family with OPMD was recently identified in Pretoria, South Africa (SA). Molecular studies revealed a (GCG)11(GCA)3GCG or (GCN)15 mutant allele. The (GCN)15 mutation detected in this family has been described previously in families from Uruguay and Mexico as a founder effect. To our knowledge, this is the first report of an SA Afrikaner family with molecularly confirmed OPMD. The proband, a 64-year-old woman, presented to the neurology outpatient department at Steve Biko Academic Hospital, Pretoria. A sibship of 18 individuals was identified, of whom eight had OPMD. Four patients were interviewed and examined clinically, and electromyographic studies were performed. Molecular analysis of the PABPN1 gene was performed by polymerase chain reaction amplification and direct sequencing of exon 1 in three of the patients. Patients presented with ptosis, external ophthalmoplegia, dysphagia, dysarthria and mild proximal weakness. High foot arches and absent ankle reflexes raised the possibility of peripheral neuropathy, but electromyography showed only mildly low sensory amplitudes, and myopathic units in two patients.