Fetal Akinesia Deformation Sequence 4 via the NUP88 Gene

Fetal akinesia (FA) describes a clinical syndromic entity characterized by reduced or absent fetal movements resulting in multiple phenotypic abnormalities. These secondary defects may include intrauterine growth restriction (IUGR), craniofacial dysmorphic features (cleft palate or retromicrognathia), limb pterygia, pulmonary hypoplasia, and arthrogryposis. This group of disorders contains several overlapping conditions ranging from distal arthrogryposis, multiple pterygium syndrome, arthrogryposis multiplex congenita (AMC), to the more severe lethal congenital contracture syndrome and fetal akinesia deformation sequence (FADS) (Beecroft et al. 2018. PubMed ID: 29959180; Pergande et al. 2020. PubMed ID: 31680123).

AMC is defined by congenital, non-progressive contractures in more than two joints and in multiple body areas. These contractures and reduced fetal movement can lead to secondary polyhydramnios or fetal hydrops. The underlying defect can be genetic or environmental. Causes can include muscle disorders, neurological disorders, connective tissue disorders, fetal vascular compromise, uterine space limitations, and maternal disease or drug use. The overall incidence of AMC ranges from 1/3,000 to 1/5,000 live births (Beecroft et al. 2018. PubMed ID: 29959180; Pergande et al. 2020. PubMed ID: 31680123).

FADS 4 has been reported in two unrelated families to date. In one family, 4 affected pregnancies were reported in which two of the fetuses were found to be homozygous for a missense variant in NUP88. Clinical features for these pregnancies included intrauterine demise in 2 pregnancies, decreased fetal movements, arthrogryposis multiplex congenita (contractures of fingers, hands, elbow, and feet), muscle atrophy, polyhydramnios and ascites, high arched palate, absent stomach bubble, severe respiratory distress, and other dysmorphic features (Bonnin et al. 2018. PubMed ID: 30543681). In an additional family, compound heterozygous variants in NUP88 were found in one affected fetus with similar features to the previous family (Bonnin et al. 2018. PubMed ID: 30543681). Genetic testing may aide in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in the NUP88 gene are associated with autosomal recessive fetal akinesia deformation sequence (FADS) 4. A missense variant, a nonsense variant, and an in-frame deletion have been reported in 3 individuals with fetal akinesia deformation sequence from 2 families (Bonnin et al. 2018. PubMed ID: 30543681). The 3 individuals included one individual with compound heterozygous NUP88 pathogenic variants and two siblings who were homozygous for a NUP88 pathogenic missense variant. To date, all pathogenic variants have been inherited from a carrier parent. No structural variants have been reported.

The NUP88 gene encodes a nuceloporin protein which is a component of the nuclear pore complex (NPC). The NPC is necessary for all trafficking between the nucleus and cytoplasm and NUP88 is found in sub-complexes on both the nuclear and cytoplasmic sides. On the nuclear side of the complex, NUP88 has been shown to bind the intermediate filament protein lamin A (Lussi et al. 2011. PubMed ID: 21289091). Disruption of NUP88 in zebrafish resulted in micrognathia, smaller head and eyes, distortion of the body axis, and aplastic swim bladder which corresponds with features seen in human fetuses with FADS (Bonnin et al. 2018. PubMed ID: 30543681). NUP88 has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality). No homozygous loss-of-function variants are reported in the gnomAD database (https://gnomad.broadinstitute.org/).

The clinical sensitivity is difficult to estimate, as to date, a limited number of cases have been described in the literature (Bonnin et al. 2018. PubMed ID: 30543681). Analytical sensitivity should be high as all pathogenic variants reported to date are detectable by sequencing.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the NUP88 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as ≥20X NGS reads or Sanger sequencing.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).