Yau Daphne, De Franco Elisa, Flanagan Sarah E, Ellard Sian, Blumenkrantz Miriam, Mitchell John J
Division of Pediatric Endocrinology Montreal Children's Hospital, McGill University Health Centre, 1001 Boulevard Decarie, Montreal, H4A 3J1, Quebec, Canada.
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter, EX2 5DW, UK.
Diagn Pathol. 2017 Jan 3;12(1):1. doi: 10.1186/s13000-016-0592-1.
Haploinsufficiency of the GATA6 transcription factor gene was recently found to be the most common cause of pancreatic agenesis, a rare cause of neonatal diabetes mellitus. Although most cases are de novo, we describe three siblings with inherited GATA6 haploinsufficiency and the rare finding of parental mosaicism.
The proband was born at term with severe intrauterine growth restriction, the first child of non-consanguineous parents. Diabetes occurred on day of life 1 with pancreatic exocrine insufficiency noted at several months of age. Pancreatic agenesis with absent gallbladder was confirmed when he underwent congenital diaphragmatic hernia and intestinal malrotation repair. A patent ductus arteriosus and pulmonary stenosis were repaired in infancy. Neurocognitive development has been normal. A second pregnancy was terminated due to tetralogy of Fallot and pulmonary hypoplasia secondary to congenital diaphragmatic hernia. The fetus also demonstrated severe pancreatic hypoplasia, gallbladder agenesis and intestinal rotation abnormalities. Despite severe hypoplasia, the pancreas demonstrated normal islet histology. Another sibling was found to have multiple cardiac abnormalities, requiring procedural intervention. Given the proband's spectrum of congenital anomalies, Sanger sequencing of the GATA6 gene was performed, revealing a novel heterozygous c.635_660del frameshift mutation (p.Pro212fs). The mutation is predicted to be pathogenic, resulting in inclusion of a premature stop codon and likely degradation of the gene transcript by nonsense-mediated decay. The abortus and the sibling with the cardiac defect were both found to have the mutation, while the father and remaining sibling were negative. The mother, who is healthy with no evidence of diabetes or cardiac disease, is mosaic for the mutation at a level of 11% in her peripheral leukocytes by next-generation sequencing.
We highlight a rare mechanism of pancreatic agenesis, this being only the second report of parental mosaicism for a GATA6 mutation and one of a handful of inherited cases. We also further define the phenotypic variability of GATA6 haploinsufficiency, even in individuals carrying the same mutation. Mutations in GATA6 should be strongly considered in cases of diabetes due to pancreatic hypoplasia or agenesis, and potentially affected family members should be tested regardless of phenotype.
最近发现GATA6转录因子基因单倍剂量不足是胰腺发育不全的最常见原因，胰腺发育不全是新生儿糖尿病的罕见病因。尽管大多数病例是新发的，但我们描述了三名患有遗传性GATA6单倍剂量不足的兄弟姐妹以及罕见的父母嵌合现象。
先证者足月出生，有严重的宫内生长受限，其父母非近亲结婚。出生第1天即出现糖尿病，几个月大时发现胰腺外分泌功能不全。在接受先天性膈疝和肠旋转不良修复手术时，证实为胰腺发育不全且胆囊缺如。婴儿期修复了动脉导管未闭和肺动脉狭窄。神经认知发育正常。第二次妊娠因法洛四联症和先天性膈疝继发的肺发育不全而终止。胎儿也表现出严重的胰腺发育不全、胆囊缺如和肠旋转异常。尽管胰腺严重发育不全，但胰岛组织学表现正常。另一名兄弟姐妹被发现有多种心脏异常，需要进行手术干预。鉴于先证者的先天性异常谱，对GATA6基因进行了桑格测序，发现一个新的杂合c.635_660del移码突变（p.Pro212fs）。该突变预计具有致病性，导致包含一个过早的终止密码子，并可能通过无义介导的衰变使基因转录本降解。流产胎儿和患有心脏缺陷的兄弟姐妹均被发现有该突变，而父亲和其余兄弟姐妹为阴性。母亲健康，无糖尿病或心脏病证据，通过下一代测序发现其外周血白细胞中该突变的嵌合率为11%。
我们强调了一种罕见的胰腺发育不全机制，这是GATA6突变的父母嵌合现象的第二篇报道，也是少数遗传性病例之一。我们还进一步明确了GATA6单倍剂量不足的表型变异性，即使是携带相同突变的个体。对于因胰腺发育不全或发育不全导致糖尿病的病例，应强烈考虑GATA6突变，无论其表型如何，潜在受影响的家庭成员都应进行检测。
