Anencephaly

A number sign (#) is used with this entry because of evidence that anencephaly (ANPH) is caused by homozygous mutation in the TRIM36 gene (609317) on chromosome 5q22. One such patient has been reported.

Description

Anencephaly is characterized by the absence of cranial vault and brain tissues in the fetus. It is considered an extreme form of neural tube defect (182940) (summary by Singh et al., 2017).

Inheritance

Penrose (1957) concluded that recessive inheritance of anencephaly exists. Multiple affected sibs were reported by several authors, e.g., Iffy (1963), who observed 3 affected sibs and quoted the description by Martin (1840) of 6 affected sibs. Record and McKeown (1950) estimated that the empiric risk of recurrence is about 2%. Concordantly affected presumably monozygotic twins were reported by Taber and Elwell (1960), Josephson and Waller (1933), and Labate and Calvelli (1952). Discordance in monozygotic twins was reported by Grebe (1949), Pedlow (1961), and Litt and Strauss (1935). Horne's patient (1958) had 4 anencephalic offspring of which the last was sired by a man other than the husband. Stevenson (1960) described 6 affected sibs. Dumoulin and Gordon (1959) reported a patient who, in addition to producing 3 normal and 2 anencephalic infants, had uniovular twins, one of whom was anencephalic. Yen and MacMahon (1968) studied the recurrence of anencephaly in families and concluded that the findings were explained by a persistent environmental factor as adequately as by genetic factors. Christakos and Simpson (1969) described anencephaly in 3 sibs.

Fuhrmann et al. (1971) described 5 of 8 children of 2 related families with spina bifida or anencephaly. The 2 fathers had married 2 sisters and each union was a third-cousin marriage.

Farag et al. (1986) reported 3 sibships in 2 kindreds with multiple cases of 'nonsyndromal' anencephaly, including 2 instances of like-sex twins concordantly affected. In 1 kindred, 2 affected sibships were offspring of consanguineous parents.

Prompted by the case of a 21-year-old woman who sought counseling after the birth of 2 consecutive anencephalic male fetuses with complete rachischisis and discordant renal dysplasia, and because of the presence of parental consanguinity, Shaffer et al. (1990) analyzed segregation in 23 additional consanguineous cases and compared the findings with those in 294 presumably nonconsanguineous families previously reported. Using classical segregation analysis, the segregation ratios in the nonsporadic cases were consistent with a major autosomal recessive locus in both groups.

Zlotogora (1995) suggested the existence of a major autosomal recessive gene responsible for anencephaly among Iranian Jews.

Molecular Genetics

In a 20-week-old fetus, born of consanguineous Indian parents, with anencephaly, Singh et al. (2017) identified a homozygous missense mutation in the TRIM36 gene (P508T; 609317.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Cellular transfection of the mutation led to disrupted microtubules, disorganized spindles, loosely arranged chromosomes, abnormal cytokinesis, decreased cell proliferation, and increased apoptosis compared to controls. Similar results were obtained by cellular knockdown of TRIM36 using siRNA. Singh et al. (2017) concluded that mutant TRIM36 adversely affects neural cell proliferation during neural tube formation, leading to anencephaly.

Population Genetics

A striking geographic variation may in part be due to ethnic genetic differences (Masterson, 1962).

Farag et al. (1989) reported a marked fall in the frequency of anencephaly among Bedouins in the last 20 years, which they attributed to a better maternal diet. A mass educational dietetic program to the Bedouin women had emphasized the importance of fresh vegetables and fruit, rich in folic acid, in addition to their traditional foods, rice and meat.

Zlotogora (1995) stated that among families originating in Iran or Iraq, anencephaly is the most prevalent neural tube defect.

Singh et al. (2017) stated that anencephaly has a prevalence of 2.1 per 1,000 births in India.

Animal Model

Zhao et al. (1996) reported that mice that are homozygous for deficiency in the paired class homeobox-containing gene Cart1 (601527, see Zhao et al., 1993) are born alive with acrania and meroanencephaly but die soon after birth. They noted that the phenotype observed in these mice resembles strikingly a corresponding human syndrome caused by a neural tube closure defect. Prenatal treatment of Cart1-deficient mutant mice with folic acid suppressed the acrania/meroanencephaly phenotype, suggesting to Zhao et al. (1996) that these mice may provide a useful animal model for developing therapeutic protocols for neural tube defects. They further reported that on the C57BL/6 x 129 hybrid genetic background approximately 65% of the Cart1-mutant mice developed the acrania/meroanencephaly, while the other 35% had fully formed heads. They also examined mutant mice on a 129/SvEv inbred genetic background. On this genetic background Zhao et al. (1996) reported that all Cart1-deficient mutants had the acrania /meroanencephaly phenotype. These results suggested to them that the penetrance of the acrania/meroanencephaly phenotype is modified by differences in genetic background.