Stokes Bethany, Berger Seth I, Hall Beth A, Weiss Karin, Martinez Ariel F, Hadley Donald W, Murdock David R, Ramanathan Subhadra, Clark Robin D, Roessler Erich, Kruszka Paul, Muenke Maximilian
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Minnesota Perinatal Physicians, Allina Health, Minneapolis, Minnesota, USA.
Congenit Anom (Kyoto). 2018 Jan;58(1):29-32. doi: 10.1111/cga.12234. Epub 2017 Aug 1.
Holoprosencephaly (HPE) is failure of the forebrain to divide completely during embryogenesis. Incomplete penetrance has not been reported previously in SIX3 whole gene deletions, which are known to cause HPE. Both chromosomal microarray and whole exome sequencing (WES) were used to evaluate families with inherited HPE. Two families showed inherited deletions that contain SIX3 and were incompletely penetrant for HPE. Using WES, we ruled out parental mosaicism, a SIX3 hypomorph, and clinically significant variants in genes that are known to interact with SIX3 as causes of incomplete penetrance. We demonstrate the importance of molecular cascade testing in families with HPE and we answer important questions about incomplete penetrance.
前脑无裂畸形（HPE）是指胚胎发育过程中前脑未能完全分裂。此前尚未有关于已知会导致HPE的SIX3全基因缺失不完全外显的报道。采用染色体微阵列和全外显子测序（WES）对患有遗传性HPE的家系进行评估。两个家系显示出包含SIX3的遗传性缺失，且HPE表现为不完全外显。通过WES，我们排除了父母嵌合体、SIX3亚效等位基因以及已知与SIX3相互作用的基因中具有临床意义的变异作为不完全外显的原因。我们证明了分子级联检测在HPE家系中的重要性，并回答了有关不完全外显的重要问题。
