MOLECULAR STUDY EPISODIC HOLOPROSENCEPHALY (SHH, ZIC2, SIX3, TGIF1) SEQUENCING, WHOLE BLOOD

New Test in CIC Catalog

Test Code: 4152

Sample:	Whole blood - EDTA (5 ml)
Conservation:	Refrigerated
Method:	Sequencing Method
Set Up Days:	Daily
Plazo de Entrega:	90 days
Information:
Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and 28th day of gestation, and affecting both the forebrain and face, which results in neurological manifestations and facial anomalies of variable severity. Prevalence is estimated to be 1/10,000 live and still births and 1/250 conceptuses. HPE has worldwide distribution. Three classical forms of HPE of increasing severity have been described based on their anatomical characteristics: lobar, semi-lobar and alobar HPE. A milder subtype known as midline interhemispheric variant (MIH) has been described. The HPE phenotype also extends to aprosencephaly/atelencephaly (the most severe end of the spectrum), schizencephaly and septopreoptic HPE (see these terms). The less severe forms are called microforms (see this term) and are characterized by midline defects without the typical HPE brain defect. There is however a continuous spectrum of abnormal separation of the hemispheres rather than clearly distinct division into these forms, with significant inter- and intrafamilial clinical variability. In most cases, there is a correlation between the severity of the facial anomalies and the brain defect (except in cases of mutation in the ZIC2 gene). In decreasing severity, the main facial features are cyclopia, proboscis, premaxillary agenesis, median or bilateral cleft lip/palate, coloboma, retinal dysplasia, choanal stenosis, pyriform sinus stenosis, hypotelorism, solitary maxillary median incisor or even normal face. Severe forms (especially in the presence of a chromosomal anomaly) are often fatal and mortality is correlated with the severity of brain malformation and associated defects. In surviving children, a wide range of associated manifestations is reported: developmental delay, hydrocephalus, motor impairment, feeding difficulties and oromotor dysfunction, epilepsy, hypothalamic dysfunction. Endocrine disorders due to pituitary defects such as central diabetes insipidus are frequent. The etiology is very heterogeneous: from chromosomal abnormalities (such as trisomy 13), known syndromes (such as Smith-Lemli-Opitz syndrome, Charge syndrome) (see these terms) to environmental factors (maternal diabetes or hypocholesterolemia during gestation). In non-chromosomal non-syndromic HPE, at least 14 genes have been implicated: 4 major genes (SHH (7q36), ZIC2 (13q32), SIX3 (2p21), TGIF (18p11)) and 10 minor genes (PTCH1 (9q22), GLI2 (2q14), FOXH1 (8q24), TDGF1 (3p21), DISP1 (1q42), NODAL (10q22), FGF8 (10q24), GAS1 (9q21), DLL1 (6q27), and CDON (11q23-q24)). Molecular analyses of the 4 main genes are routinely performed with a mutation detection rate of 25%. Array-CGH (comparative genomic hybridization) analysis shows 22% micro-rearrangements in HPE. However, the genetic complexity underlying HPE is yet to be clarified. Most severe cases are detected by systematic ultrasound scan and magnetic resonance imaging (MRI) during pregnancy. Subsequently, diagnosis is based on clinical features. Differential diagnosis includes anencephaly, severe congenital hydrocephalus, Walker-Warburg syndrome (see these terms), large interhemispheric cyst, otocephaly and other midline defects. Due to the high clinical variability, prenatal diagnosis is based on ultrasound scans and MRI rather than on molecular diagnosis, and may be useful in mothers with diabetes and those with a family history of HPE. Genetic counseling is particularly complex in HPE. Treatment is symptomatic and supportive, and requires a multidisciplinary approach. Prognosis depends on severity and the associated complications.
Links:
OMIM Entry - % 236100 - HOLOPROSENCEPHALY
Orphanet- Holoprosencephaly
OMIM Entry - - 600725 - SONIC HEDGEHOG; SHH
OMIM Entry - - 602630 - TRANSFORMING GROWTH FACTOR-BETA-INDUCED FACTOR; TGIF
OMIM Entry - - 603073 - ZINC FINGER PROTEIN OF CEREBELLUM 2; ZIC2
OMIM Entry - - 603714 - SINE OCULIS HOMEOBOX, DROSOPHILA, HOMOLOG OF, 3; SIX3

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