Khan-Khan-Katsanis Syndrome

A number sign (#) is used with this entry because of evidence that Khan-Khan-Katsanis syndrome (3KS) is caused by homozygous or compound heterozygous mutation in the NCAPG2 gene (608532) on chromosome 7q36.

Description

Khan-Khan-Katsanis syndrome (3KS) is an autosomal recessive neurodevelopmental disorder with variable involvement of the ocular, renal, skeletal, and sometimes cardiac systems. Affected individuals present at birth with multiple congenital anomalies, defects in urogenital and limb morphogenesis, poor overall growth with microcephaly, and global developmental delay (summary by Khan et al., 2019).

Clinical Features

Khan et al. (2019) reported 2 unrelated girls with a complex syndromic neurodevelopmental disorder. The phenotypes were somewhat different, but the patients shared several core features, including poor overall growth with microcephaly, renal and skeletal abnormalities, and developmental delay. Both pregnancies were complicated by advanced maternal age (37 and 39 years). Patient 1, of European American origin, was 11 years old, whereas patient 2, of Mexican origin, had died of unknown causes at 4 months of age. Patient 1 had normal growth parameters at term birth, but later showed failure to thrive and microcephaly, whereas patient 2 presented with severe intrauterine growth retardation and premature birth (34 weeks' gestation). Patient 1 had a 2-vessel cord, severe hypotonia, postaxial polydactyly of the feet, sacral dimple with tethered cord, scoliosis, short stature, and bilateral grade IV vesicoureteral reflux. She had delayed development, acquired walking at 6 years of age, and showed moderately impaired intellectual development with absent speech; she also had mild, late-onset sensorineural hearing loss. She was monitored for renal structure and function since birth, but by age 10, she had only a small right kidney and ureteral duplication; other imaging abnormalities had resolved. Brain imaging revealed mild volume loss, colpocephaly, and hypoplasia of the cerebellar vermis. Additional features included frontal bossing, short nose with tented, triangular mouth, underdeveloped/absent clitoris, and abnormally placed anus. She also had multiple ocular anomalies, including strabismus, nystagmus, epiblepharon, corneal scarring, and pigmentary retinopathy resulting in visual impairment. Patient 2 had multiple congenital anomalies, including microcephaly, facial dysmorphism with micrognathia, digital abnormalities (postaxial absent toes and clinodactyly of the fifth finger), left-sided contractures, neonatal hypertonia, and a sacral dimple accompanied by a low-lying conus medullaris. She had several ocular anomalies, including Peters anomaly, bilateral glaucoma, buphthalmos of the left eye, and visual impairment. She also had variable cardiovascular defects, such as patent ductus arteriosus, patent foramen ovale, mild tricuspid regurgitation, and bilateral superior vena cava with an absent bridging vein. Renal ultrasound initially showed small kidneys, and she later developed hydronephrosis that resolved. The patient had oropharyngeal dysphasia necessitating a gastric tube; she died of unknown causes at age 4 months.

Inheritance

The transmission pattern of 3K syndrome in the families reported by Khan et al. (2019) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated girls with 3K syndrome, Khan et al. (2019) identified homozygous or compound heterozygous missense mutations in the NCAPG2 gene (608532.0001-608532.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Lymphocytes derived from 1 of the patients showed normal NCAPG2 protein levels, and patient-derived fibroblasts showed normal localization of NCAPG2 to the nucleus. However, patient fibroblasts showed increased apoptosis with a 6-fold increase in cell death compared to controls. This was associated with multiple abnormalities during mitosis, including impaired chromosomal condensation, lagging chromatin fragments and chromatin bridges, and increased numbers of micronuclei compared to controls. Cell cycle studies revealed increased G2/M arrest in patient cells. Expression of the mutations was unable to rescue the decreased head size or renal defects in zebrafish with knockdown of the ncapg2 gene, suggesting that all variants resulted in a loss of function. Patient 1 also carried a paternally-inherited heterozygous deletion that encompassed the NPHP1 gene (607100), which may have contributed to the phenotype.

Animal Model

Smith et al. (2004) found that targeted disruption of Mtb in mice resulted in embryos that died immediately following implantation. The lethality was due to a defect in expansion of the inner cell mass, as Mtb null blastocysts failed to exhibit outgrowth of the inner cell mass both in vitro and in vivo. Furthermore, Mtb null blastocysts exhibited a higher frequency of apoptotic cells than wildtype or heterozygous blastocysts.

Khan et al. (2019) found that knockdown of the ncapg2 gene in zebrafish, using both morpholino knockdown and CRISPR/Cas9 genome editing, resulted in a dose-dependent significant reduction in head size and anterior brain structures compared to controls. These defects were associated with altered cell cycle progression and increased apoptosis. In addition, mutant animals showed several renal abnormalities, including renal aplasia, hypoplastic renal tubules, and enlarged renal tubule diameter compared to controls. The abnormalities could be rescued by expression of wildtype human NCAPG2.