Preimplantation Embryonic Lethality 1

A number sign (#) is used with this entry because of evidence that preimplantation embryonic lethality-1 (PREMBL1) is caused by homozygous mutation in the TLE6 gene (612399) on chromosome 19p13.

Description

Maternal genes play a critical role in the very early stages of embryonic development because of the lag in transcribing genes derived from the male pronucleus. TLE6 mutations are a rare cause of human female-limited fertility and appear to represent the earliest known human embryonic lethality that is due to a single gene mutation. In affected women, ovulation proceeds normally and the retrieved oocytes appear normal, but zygote formation is severely impaired (Alazami et al., 2015).

Genetic Heterogeneity of Preimplantation Embryonic Lethality

Preimplantation embryonic lethality-2 (PREMBL2; 617234) is caused by mutation in the PADI6 gene (610363) on chromosome 1p36.

Clinical Features

Alazami et al. (2015) studied 3 infertile women from 2 consanguineous Saudi families. In the first family, 2 sisters with primary infertility had each previously undergone 4 unsuccessful intracytoplasmic sperm injection (ICSI) cycles. At ages 26 years and 36 years, they underwent another 5 cycles, with successful stimulation and retrieval of 58 oocytes. Only 3 oocytes developed 2 pronuclei indicating normal fertilization; those zygotes had developmental arrest at the 1-, 2-, and 4-cell stage, respectively. The 2 sisters had a number of brothers and sisters who were healthy and fertile. In the second family, the proband presented at age 30 years for treatment of primary infertility, with a pattern of in vitro fertilization failure similar to that of the 2 sisters. She underwent 2 ICSI cycles with a total of 19 oocytes injected, which resulted in no zygote formation.

Mapping

By linkage analysis in 3 infertile women from 2 consanguineous Saudi families that were not known to be related, Alazami et al. (2015) identified a shared autozygous interval on chromosome 19p13 (chr19:2,712,016-3,918,047, GRCh37) with a lod score of 4.17. Alazami et al. (2015) noted that the identical haplotype indicated the presence of a common ancestor, consistent with the shared geographic location of the families.

Molecular Genetics

In 2 sisters from a consanguineous Saudi family with primary infertility due to preimplantation embryonic lethality, Alazami et al. (2015) performed whole-exome sequencing and identified homozygosity for a missense mutation in the TLE6 gene (S510Y; 612399.0001). In addition, an affected woman from a different Saudi family was homozygous for the S510Y mutation. The phenotype was gender-specific, since a fertile brother was also homozygous for S510Y in 1 of the families. The mutation was found once in heterozygous state in 615 in-house Saudi exomes (allele frequency less than 0.001) and was not found in the 1000 Genomes Project and Exome Variant Server databases.