Molecular genetics of holoprosencephaly

Nanni, Luisa; Rl, Schelper; Mt, Muenke

doi:10.2741/nanni

Cited by 26 publications

(11 citation statements)

References 43 publications

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“…Approximately, 50% of HPE cases are associated with a cytogenetic abnormality or a monogenic syndrome. At least 12 genetic loci contain genes implicated in the pathogenesis of HPE, such as locus SHH at 7q36 and ZIC2 at 13q32 among others [Roessler et al, 1996; Brown et al, 1998; Nanni et al, 2001]. The form of HPE associated with chromosomal aberrations in the 7q36 region was designated as HPE type 3.…”

Section: Discussionmentioning

confidence: 99%

Risk evaluation of carriers with chromosome reciprocal translocation t(7;13)(q34;q13) and concomitant meiotic segregation analyzed by FISH on ejaculated spermatozoa

Midro

Wiland

Panasiuk

et al. 2006

American J of Med Genetics Pt A

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We performed the segregation analysis of a relatively large pedigree of t(7;13)(q34;q13) carriers together with the sperm karyotype analysis of the one carrier using a tri-color fluorescence in situ hybridization (FISH) method. The risk assessments for unfavorable pregnancy outcomes in a series of 36 pregnancies in eight reciprocal chromosome translocation (RCT) couples of carriers were estimated directly from a pedigree after ascertainment correction. The individual probability rate for unbalanced child was predicted according to Stengel-Rutkowski and co-workers. The unbalanced karyotypes in the form of monosomy 7q34-->qter and trisomy 13q13-->qter were detected among stillborn/early death newborns with holoprosencephaly (HPE), cyclopia and other malformations. Based on clinical description of unkaryotyped stillbirth progeny, it can be assumed that the phenotype distinctions were connected with the unbalanced karyotype from 2:2 segregation (monosomy 7q with trisomy 13q) and 3:1 segregation as interchange trisomy 13 (Patau syndrome). Probability rates for miscarriages, stillbirth/early death were 12.9 +/- 6% (4/31) and 29 +/- 8.2% (9/31), respectively. The results of the meiotic segregation pattern indicated the rate of unbalanced spermatozoa for about 60%, with the unusual high rate (29.4%) of 3:1 segregant (i.e., 13.4% of the tertiary segregation and 16% of the interchange segregation). Adjacent-1 segregation followed with 23.5% and adjacent-2 followed with 7.2% of analyzed spermatozoa. The high rate of unbalanced gametes in comparison to the number of stillborn/early death and miscarriages detected in pedigree suggests a strong selection against unbalanced chromosomal constitutions during fetal development. It corresponds to a very small probability rate (about 0.3%) of viable unbalanced progeny from 3:1 meiotic segregation predicted for maternal carriers. This knowledge can be used in genetic counseling of families with similar RCT ascertained in a different way.

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Section: Discussionmentioning

confidence: 99%

Risk evaluation of carriers with chromosome reciprocal translocation t(7;13)(q34;q13) and concomitant meiotic segregation analyzed by FISH on ejaculated spermatozoa

Midro

Wiland

Panasiuk

et al. 2006

American J of Med Genetics Pt A

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“…It was shown that mutations in the human TGIF1 gene were associated with HPE (Gripp et al 2000). Thus, the HPE with cyclopia is caused by both the partial loss of 18p where the HPE4 locus resides (Nanni et al 2000), and a triplication of 18q genes.…”

Section: Development Of the Craniummentioning

confidence: 99%

Genetically induced abnormal cranial development in human trisomy 18 with holoprosencephaly: comparisons with the normal tempo of osteogenic–neural development

2015

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Craniofacial malformations are common congenital defects caused by failed midline inductive signals. These midline defects are associated with exposure of the fetus to exogenous teratogens and with inborn genetic errors such as those found in Down, Patau, Edwards' and Smith-Lemli-Opitz syndromes. Yet, there are no studies that analyze contributions of synchronous neurocranial and neural development in these disorders. Here we present the first in-depth analysis of malformations of the basicranium of a holoprosencephalic (HPE) trisomy 18 (T18; Edwards' syndrome) fetus with synophthalmic cyclopia and alobar HPE. With a combination of traditional gross dissection and state-of-the-art computed tomography, we demonstrate the deleterious effects of T18 caused by a translocation at 18p11.31. Bony features included a single developmentally unseparated frontal bone, and complete dual absence of the anterior cranial fossa and ethmoid bone. From a superior view with the calvarium plates removed, there was direct visual access to the orbital foramen and hard palate. Both the eyes and the pituitary gland, normally protected by bony structures, were exposed in the cranial cavity and in direct contact with the brain. The middle cranial fossa was shifted anteriorly, and foramina were either missing or displaced to an abnormal location due to the absence or misplacement of its respective cranial nerve (CN). When CN development was conserved in its induction and placement, the respective foramen developed in its normal location albeit with abnormal gross anatomical features, as seen in the facial nerve (CNVII) and the internal acoustic meatus. More anteriorly localized CNs and their foramina were absent or heavily disrupted compared with posterior ones. The severe malformations exhibited in the cranial fossae, orbital region, pituitary gland and sella turcica highlight the crucial involvement of transcription factors such as TGIF, which is located on chromosome 18 and contributes to neural patterning, in the proper development of neural and cranial structures. Our study of a T18 specimen emphasizes the intricate interplay between bone and brain development in midline craniofacial abnormalities in general.

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“…HPE is a result of abnormal forebrain development during embryogenesis. It is characterized by a lack of, or incomplete division of, the prosencephalon into the telencephalon and diencephalon, separate cerebral hemispheres, and optic and olfactory bulbs [Nanni et al, 2000]. The result is apposition of structures that would normally divide into separate entities.…”

Section: Introductionmentioning

confidence: 99%

Partial deletions of the long arm of chromosome 13 associated with holoprosencephaly and the Dandy‐Walker malformation

McCormack¹,

Shen²,

Curry³

et al. 2002

Am. J. Med. Genet.

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Two patients with partial deletions of the long arm of chromosome 13, del(13)(13q21-q34) and del(13)(13q22-q33), respectively, multiple congenital anomalies including holoprosencephaly (HPE) and the Dandy-Walker malformation (DWM) are described. The occurrence of HPE and the DWM in both of these patients suggests that, in addition to ZIC2, which is important for normal development of the forebrain, there is at least one other dosage-sensitive gene in 13q22-q33 that plays an important role in brain development. The DWM is anatomically and developmentally distinct from HPE. The presence of a DWM in each of these two patients with partial deletions of the long arm of chromosome 13 suggests that haploinsufficiency at a locus in 13q22-q33 may cause this anomaly. These findings suggest that microdeletions in 13q22-q33 may be found in a proportion of patients with an apparently isolated DWM. Therefore, careful high-resolution cytogenetic analysis (550 band level or greater) of 13q22-q33 may be considered in these patients. Furthermore, future molecular studies of this region may reveal candidate gene loci for the DWM.

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Molecular genetics of holoprosencephaly

Cited by 26 publications

References 43 publications

Risk evaluation of carriers with chromosome reciprocal translocation t(7;13)(q34;q13) and concomitant meiotic segregation analyzed by FISH on ejaculated spermatozoa

Risk evaluation of carriers with chromosome reciprocal translocation t(7;13)(q34;q13) and concomitant meiotic segregation analyzed by FISH on ejaculated spermatozoa

Genetically induced abnormal cranial development in human trisomy 18 with holoprosencephaly: comparisons with the normal tempo of osteogenic–neural development

Partial deletions of the long arm of chromosome 13 associated with holoprosencephaly and the Dandy‐Walker malformation

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