Neurodevelopmental Disorder, X-Linked, With Craniofacial Abnormalities

A number sign (#) is used with this entry because of evidence that X-linked neurodevelopmental disorder with craniofacial abnormalities (NEDXCF) is caused by heterozygous or hemizygous mutation in the STAG2 gene (300826) on chromosome Xq25.

Description

X-linked neurodevelopmental disorder with craniofacial abnormalities is characterized by global developmental delay with impaired intellectual development and poor speech. Ear abnormalities and hearing loss are common, as are dysmorphic facial features such as microcephaly and cleft palate. Other features may include short stature, scoliosis, vertebral abnormalities, and mild limb abnormalities such as fifth finger clinodactyly. Clinical manifestations depend on the type of mutation: female carriers with missense mutations may be unaffected, and conversely, males with nonsense or truncating mutations may have a severe phenotype with early death (summary by Aoi et al., 2019).

Clinical Features

Female Patients

Mullegama et al. (2017) reported an 8-year-old girl of Latino/Hispanic descent (patient 1) with global developmental delay, progressive microcephaly, microtia with hearing loss, speech and language delay, attention deficit-hyperactivity disorder, and poor overall growth. She walked and spoke her first words at 18 months. Dysmorphic features included borderline microcephaly, low anterior hairline, sloping forehead, left preauricular pit and tag, small left eye, asymmetric facial movements, and submucous cleft palate with bifid uvula. CT of the temporal bones showed several abnormalities on both sides, including left external auditory canal atresia with a fused ossicular mass, bilateral absent stapes, stenosis or absence of the oval windows, and abnormal placement of the facial nerves. Other features included fifth finger clinodactyly, scoliosis, vertebral body abnormalities, and dysgenesis of the splenium of the corpus callosum. Two additional unrelated girls with a similar phenotype were subsequently identified in the DECIPHER database. Clinical details were limited, but the girls were noted to have developmental delay, craniofacial, and limb or skeletal abnormalities.

Yuan et al. (2019) reported 4 unrelated girls with NEDXCF who had developmental delay with impaired intellectual development, speech delay, hypotonia, microcephaly, and short stature. Variable dysmorphic features included micrognathia, long curly eyelashes, depressed or broad nasal bridge, bulbous nasal tip, dysmorphic ears, thin upper lip, and long smooth philtrum. Only 1 had conductive hearing loss. Two patients had congenital diaphragmatic hernia and 1 had hypoplastic left heart with ventricular septal defect and coarctation of the aorta. Other variable features included scoliosis, vertebral abnormalities, and fifth finger clinodactyly.

Aoi et al. (2019) reported a 7-year-old Japanese girl (patient 2) with global developmental delay, impaired intellectual development, sensorineural hearing loss, and white matter hypoplasia. Dysmorphic features included cleft palate and long philtrum. She developed seizures at 8 months, which were responsive to medication. At age 7, she had only a few words and attended a school for hearing-impaired children.

Male Patients

Soardi et al. (2017) reported a large Brazilian family in which 5 males had a similar neurodevelopmental disorder. The proband was first seen at age 29 years. He had moderately impaired intellectual development, short stature, cleft palate, unilateral sensorineural deafness, and dysmorphic features, including large nose, prominent eyes, and frontal baldness. The other 4 affected males had a similar phenotype. Obligate female mutation carriers in the family were unaffected.

Yuan et al. (2019) reported a 5-year-old male (patient 11) with failure to thrive, short stature, microcephaly, and developmental delay. He also had dysmorphic craniofacial features with cleft lip and palate and scoliosis. He had dysmorphic low-set ears, but did not have hearing loss.

Mullegama et al. (2019) reported a 4-year-old boy, born of unrelated parents, with developmental delay, failure to thrive, short stature, foot polydactyly, and pes planus. He walked at 16 months, used small phrases at 17 months, and later showed an unsteady gait with lower limb hypotonia, as well as speech difficulties. Dysmorphic features included microcephaly (less than first percentile), high anterior hairline, mild frontal bossing, prominent cheeks, triangular face, and fifth finger clinodactyly. Brain imaging and audiology testing were normal.

Aoi et al. (2019) reported a male fetus (patient 1), conceived of unrelated Japanese parents, who was noted on prenatal ultrasound at 15 weeks' gestation to have holoprosencephaly, blepharophimosis, cleft lip and palate, absence of the nasal bone, and hypoplastic left heart. The pregnancy was terminated due to multiple fetal abnormalities.

Inheritance

The transmission pattern of NEDXCF in the family reported by Soardi et al. (2017) was consistent with X-linked recessive inheritance.

Molecular Genetics

In an 8-year-old girl (patient 1) with NEDXCF, Mullegama et al. (2017) identified a de novo heterozygous nonsense mutation in the STAG2 gene (R69X; 300826.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was predicted to encode a protein lacking 3 essential protein domains. Western blot analysis of patient cells showed decreased amounts of STAG2 protein compared to controls, and the authors noted that the mutation may trigger nonsense-mediated mRNA decay. Analysis of metaphase in patient cells showed a reduction in premature sister chromatid separation compared to controls, although karyotypes were normal and there were no significant aneuploidies. Mullegama et al. (2017) postulated a loss-of-function mechanism causing haploinsufficiency, and noted that some of STAG2's other functions, such as the regulation of gene expression, may also be disrupted by the mutation. Subsequent searching of the DECIPHER database identified 2 additional girls with overlapping clinical features who had de novo heterozygous variants in the STAG2 gene (R604Q and c.1913_1922del). None of the variants were present in the 1000 Genomes Project or ExAC databases, but functional studies of the latter 2 mutations were not performed.

In 5 affected males from a large Brazilian family with NEDXCF, Soardi et al. (2017) identified a hemizygous missense mutation in the STAG2 gene (S327N; 300826.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. There were at least 2 confirmed healthy females carriers of the mutation. Analysis of patient fibroblasts showed that the mutant protein was expressed in normal amounts and localized properly to the nucleus, similar to wildtype, and there were no defects in sister chromatid cohesion. However, patient cells showed cell cycle abnormalities, including increased percentage of G2/M cells and upregulation of genes involved in cell division, mitotic regulation, and DNA replication compared to controls. These findings were consistent with a defect in transcriptional regulation. Expression of the mutation in HeLa cells showed decreased binding of the mutant protein to SCC1 and other cohesin regulators.

In a 4-year-old boy with NEDXCF, Mullegama et al. (2019) identified a de novo hemizygous missense mutation in the STAG2 gene (K1009N; 300826.0003). The mutation was found by exome sequencing; functional studies of the variant and studies of patient cells were not performed. Mullegama et al. (2019) postulated that females, who carry 2 copies of the STAG2 gene, are able to survive with deleterious de novo variants, but show severe phenotypes. In contrast, males, who have only 1 copy of the gene, are unable to survive with similar variants due to early embryonic lethality. Males can survive with less damaging variants, such as missense mutations, and usually present with a milder phenotype.

Yuan et al. (2019) reported 5 unrelated patients, including 4 females and 1 male, with NEDXCF who had de novo heterozygous or hemizygous mutations in the STAG2 gene (see, e.g., 300826.0004-300826.0006). Three of the 4 females had truncating mutations, whereas the male had a missense mutation; none of the mutations were found in the ExAC or Exome Sequencing Project databases. Yuan et al. (2019) postulated loss of function as the presumed mechanism, although functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from a large cohort of over 10,000 patients referred for exome sequencing.

Aoi et al. (2019) identified 2 nonsense mutations in the STAG2 gene in 2 unrelated Japanese patients with NEDXCF. A male fetus (patient 1) was hemizygous for R1033X (300826.0007) and a 7-year-old girl (patient 2) was heterozygous for W743X (300826.0008). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants were not performed, but the female patient showed skewed X-inactivation with expression of STAG2 only from the wildtype allele. Aoi et al. (2019) noted that no males with nonsense or frameshift STAG2 mutations had previously been reported, consistent with the hypothesis that hemizygous truncating mutations cause a severe fetal phenotype and/or embryonic lethality in males.