Holoprosencephaly (HPE) is the most common malformation of the brain and face in humans (1 in 250 fetuses, and 1/16,000 live births). It is extremely genetically heterogeneous with over 80% of HPE genes presently unknown. Generally, its etiology is attributed to either de novo or autosomal dominant inheritance of deleterious mutations (or deletions) of at least a dozen different HPE genes. Clinically, it displays incomplete penetrance, and its expressivity is extremely variable. HPE can range from a single eye (cyclopia) and un-divided forebrain, at one extreme, to simple microforms, consisting of isolated subtle facial manifestations such as a single central incisor. We have been leaders in the identification of HPE genes and confirming disease mechanisms. However, despite these advances, its etiology, pathogenesis and any explanations for the underlying genetic and environmental sources of this variability are incomplete. Therefore, there are many challenges ahead. Our past efforts have helped formulate the most comprehensive molecular and clinical descriptions of HPE. In doing so, weve synergized efforts between intramural and extramural scientists and clinicians, set evolving diagnostic standards, and established successful international collaborative efforts aimed at future progress in HPE research and related conditions. Our studies guide an understanding of both normal and abnormal brain development. The best summary of our successes can be found in our Amer J Med Genet issue 154C, which is devoted exclusively to HPE. This issue illustrates our insistence on a multi-disciplinary, multi-center approach to the description of the clinical/molecular spectrum of HPE and the genotype-phenotype associations with individual genes. During the past year we published several papers demonstrating that: 1.- Missense variants in BOC function as modifiers in HPE. 2.-SIX3 copy number variants can be associated with incomplete penetrance in HPE, just as point mutations and small indels have be reported in the past. 3.- SHH signaling defects predispose to fatty liver in humans and mice. This is important because s HPE has traditionally been considered an above-the-neck condition, and fatty liver disease is associated with other health risks that might have historically been neglected in families affected by HPE. 4.- Individuals with various HPE subtypes can survive into adulthood and the neurodevelopmental outcomes are variable. Factors associated with long-term survival include HPE subtypes other than alobar, female gender, nontypical facial features, and potentially, ZIC2 mutations. As individuals with HPE get older, special concern should be given to spasticity-related complications, and psychiatric and ophthalmic abnormalities that may not be present during childhood. 5.- Loss-of-function mutations in ROBO1 are associated with tetralogy of Fallot and septal defects. 6.- Loss-of-fucntion mutations in ZNF462 are associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay. ZNF462 is an important transcription factor in embryonic development, and is associated with craniofacial and neurodevelopmental abnormalities in humans. 7.- Bi-allelic mutations in cytosolic isoleucyl-tRNA synthetase (IARS) have been described in three individuals with growth delay, hepatic dysfunction, and neurodevelopmental disabilities. 8.- PPP1R15B deficiency is associated with infantile cirrhosis, growth impairment, and neurodevelopmental anomalies. Future studies will include efforts to identify novel HPE genes, the establishment of genotype-phenotype correlations, the study of embryological disease mechanisms, as well as gene-environment interactions.
| Roessler, Erich; Hu, Ping; Muenke, Maximilian (2018) Holoprosencephaly in the genomics era. Am J Med Genet C Semin Med Genet 178:165-174 |
| Kruszka, Paul; Muenke, Maximilian (2018) Syndromes associated with holoprosencephaly. Am J Med Genet C Semin Med Genet 178:229-237 |
| Hong, Sungkook; Hu, Ping; Roessler, Erich et al. (2018) Loss-of-function mutations in FGF8 can be independent risk factors for holoprosencephaly. Hum Mol Genet 27:1989-1998 |
| Hadley, Donald W; Kruszka, Paul; Muenke, Maximilian (2018) Challenging issues arising in counseling families experiencing holoprosencephaly. Am J Med Genet C Semin Med Genet 178:238-245 |
| Roessler, Erich; Hu, Ping; Marino, Juliana et al. (2018) Common genetic causes of holoprosencephaly are limited to a small set of evolutionarily conserved driver genes of midline development coordinated by TGF-?, hedgehog, and FGF signaling. Hum Mutat 39:1416-1427 |
| Weiss, Karin; Kruszka, Paul S; Levey, Eric et al. (2018) Holoprosencephaly from conception to adulthood. Am J Med Genet C Semin Med Genet 178:122-127 |
| Abe, Yu; Kruszka, Paul; Martinez, Ariel F et al. (2018) Clinical and Demographic Evaluation of a Holoprosencephaly Cohort From the Kyoto Collection of Human Embryos. Anat Rec (Hoboken) 301:973-986 |
| Hu, Tommy; Kruszka, Paul; Martinez, Ariel F et al. (2018) Cytogenetics and holoprosencephaly: A chromosomal microarray study of 222 individuals with holoprosencephaly. Am J Med Genet C Semin Med Genet 178:175-186 |
| Stokes, Bethany; Berger, Seth I; Hall, Beth A et al. (2018) SIX3 deletions and incomplete penetrance in families affected by holoprosencephaly. Congenit Anom (Kyoto) 58:29-32 |
| Hu, Ping; Martinez, Ariel F; Kruszka, Paul et al. (2018) Low-level parental mosaicism affects the recurrence risk of holoprosencephaly. Genet Med : |
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