A number sign (#) is used with this entry because of evidence that ventriculomegaly and arthrogryposis (VENARG) is caused by homozygous mutation in the KIDINS220 gene (615759) on chromosome 2p25.

Ventriculomegaly and arthrogryposis (VENARG) is a severe autosomal recessive congenital disorder characterized by the onset of features in utero that are not compatible with life. Affected pregnancies are terminated spontaneously or by plan due to the severity of the defects. Prenatal ultrasound and autopsy show limb contractures consistent with arthrogryposis and enlarged brain ventricles that may be associated with hydrocephalus, abnormalities of the corpus callosum, and cerebellar hypoplasia. Some affected fetuses may also have congenital heart disease and hydrops fetalis (summary by Mero et al., 2017 and El-Dessouky et al., 2020).

Mero et al. (2017) reported a consanguineous family in which 4 fetuses had VENARG resulting in intrauterine death or termination of the pregnancy. Prenatal ultrasound and autopsy findings showed dilated cerebral ventricles, sometimes with hydrocephalus, small cerebellum, corpus callosum defects, and thin cortex. All also had limb contractures. One was noted to have micrognathia.

El-Dessouky et al. (2020) reported a consanguineous Egyptian family in which several fetuses were affected with VENARG. The proband was noted to have hydrops fetalis associated with polyhydramnios, arthrogryposis multiplex congenita, ventriculomegaly, agenesis of the corpus callosum, and cerebellar hypoplasia on ultrasound at 24 weeks' gestation. Pterygia were not noted. The fetus also had congenital heart defects, including septal defects and ventricular hypertrophy. Also noted were dysmorphic facial features, including midface hypoplasia, prominent forehead, hypertelorism, depressed nasal bridge, downslanting palpebral fissures, micrognathia, and low-set ears. The pregnancy was terminated, and the imaging findings were confirmed on autopsy. Obstetric history of the mother included 8 repeated spontaneous miscarriages at 8-12 weeks' gestation, as well as another pregnancy with clinical features similar to the proband; this pregnancy was terminated at 26 weeks' gestation. The mother reported decreased fetal movements during these pregnancies.

Jacquemin et al. (2020) reported a consanguineous Pakistani family in which 3 sib fetuses were affected with VENARG. Prenatal imaging showed severe ventriculomegaly with enlarged ventricles, which was confirmed at autopsy. There was also cortical atrophy and poorly defined or absent gyri, suggesting lissencephaly. The fetuses also had generalized limb contractures with clenched hands, bent wrists, and clubfeet. The defects caused fetal death or resulted in planned termination.

The transmission pattern of VENARG in the family reported by Mero et al. (2017) was consistent with autosomal recessive inheritance.

In 3 sib fetuses, conceived of consanguineous parents, with VENARG, Mero et al. (2017) identified a homozygous frameshift mutation in the KIDINS220 gene (615759.0005). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Studies of parental cells indicated that the mutation disrupted a splice site and would likely induce nonsense-mediated mRNA decay. The findings were consistent with a complete loss of function, although additional functional studies were not performed.

In a fetus, conceived of consanguineous Egyptian parents, with VENARG, El-Dessouky et al. (2020) identified a homozygous frameshift mutation in the KIDINS220 gene (615759.0006). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the unaffected parents. The mutation was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.

In 3 fetuses, conceived of consanguineous Pakistani parents, with VENARG, Jacquemin et al. (2020) identified a homozygous in-frame deletion in the KIDINS220 gene (615759.0007). The mutation, which was found by exome sequencing, was present in heterozygous state in the unaffected parents. It was not present in the gnomAD database. In vitro functional expression studies in HEK293 cells transfected with the mutation showed that it interfered with the interaction between KIDINS220 and TRKA (NTRK1; 191315), which the authors suggested may have a detrimental impact on downstream signaling pathways involved in development. Studies of patient cells were not performed.