A number sign (#) is used with this entry because of evidence that X-linked syndromic intellectual developmental disorder-37 (MRXS37) is caused by hemizygous or heterozygous mutation in the ZFX gene (314980) on chromosome Xp22.

X-linked syndromic intellectual developmental disorder-37 (MRXS37) is a developmental disorder showing phenotypic variability and variable severity. Male mutation carriers tend to be more severely affected than female mutation carriers, some of whom may even be asymptomatic. In general, the disorder is characterized by global developmental delay with delayed walking, speech delay, impaired intellectual development that ranges from borderline low to moderate, and behavioral abnormalities, such as autism and sleeping difficulties. Many patients are able to attend mainstream schools with assistance and work under supervision. Additional more variable features include sensorineural hearing loss, ocular anomalies, feeding difficulties, dysmorphic facial features, inguinal and umbilical hernia, genitourinary defects, congenital heart defects, musculoskeletal anomalies, and endocrine dysfunction, such as hypogonadism or hyperparathyroidism (Shepherdson et al., 2024).

Shepherdson et al. (2024) reported 18 patients, including 14 males and 4 females, from 16 unrelated families with an X-linked syndromic neurodevelopmental disorder associated with mutations in the ZFX gene. Half of the patients were born by C-section, and 33% were born prematurely. Some were small for gestational age and later showed short stature, whereas others had macrosomia. Many had early feeding problems, including gastroesophageal reflux, pyloric stenosis, and constipation. Almost all patients, who ranged from 8 to 34 years of age, had global developmental delay with hypotonia, motor delay, delayed walking, speech delay, impaired intellectual development, and behavioral abnormalities, such as autism, ADHD, anger, frustration, and sleep difficulties. Level of intellectual disability ranged from low-normal to moderate; most males were able to attend mainstream schools with assistance or special education, with mathematics being particularly difficult, and some of the older patients could hold supervised jobs. Two of the 4 female mutation carriers were described as very intelligent, and 2 had mild learning disabilities. About half had sensorineural or conductive hearing loss (the latter associated with recurrent otitis media), and most had variable ocular anomalies, including refractive errors, strabismus, astigmatism, nystagmus, and optic nerve hypoplasia. Dysmorphic facial features included coarse facies with high prominent forehead, metopic ridging, midface hypoplasia, macrocephaly, long or smooth philtrum, long face, pointed chin, downslanting palpebral fissures, epicanthal folds, micrognathia, wide mouth, thin upper lip, macroglossia, high palate, large, low-set, and posteriorly rotated ears, thick eyebrows, synophrys, depressed nasal bridge, and bulbous nasal tip. All but 1 had skeletal anomalies, mainly affecting the hands and feet with abnormal shapes of the digits, deep-seated nails, and hallux valgus, as well as joint hypermobility, scoliosis, and pectus abnormalities. Genital anomalies were also common, including hypospadias, cryptorchidism, inguinal and umbilical hernia, and mild renal defects. About 57% had structural cardiac defects. Ten (77%) of 13 patients who underwent brain imaging showed nonspecific abnormalities, including cerebral atrophy, arachnoid cysts, delayed myelination, corpus callosum anomalies, and cerebellar atrophy. A few patients, particularly older female mutation carriers, had hyperparathyroidism or hypercalcemia. Tumors and vascular anomalies were observed in several patients; these included hemangiomas, hepatic angiomatosis or adenoma, melanocytic nevi, colorectal adenocarcinoma, sarcoma, and thyroid papillary carcinoma.

The transmission pattern of MRXS37 in the families reported by Shepherdson et al. (2024) was consistent with X-linked inheritance with variable expressivity. Male mutation carriers tended to be more severely affected than female mutation carriers. Female mutation carriers showed skewed X inactivation.

In 18 individuals, including 14 males and 4 females, from 14 unrelated families with MRXS37, Shepherdson et al. (2024) identified heterozygous mutations in the ZFX gene (see, e.g., 314980.0001-314980.0005). The mutations, which were identified through exome sequencing, were not present in the gnomAD database. Four missense variants were identified in 11 individuals (including 3 individuals in family 6), and 7 frameshift mutations were identified in the 7 other patients. Ten patients had de novo mutations, whereas 8 inherited the mutation from a mildly affected or unaffected mother. Of note, 8 individuals carried variants affecting other genes that may have contributed to the phenotype. The missense ZFX mutations clustered in the penultimate and ultimate zinc-finger domains, which are critical for DNA-binding activity. Expression of the missense variants in ZFX-null HEK293 cells showed that they had similar DNA binding patterns to wildtype, although some showed subtle alterations in DNA binding. RNA-seq analysis of cells carrying the missense variants showed evidence of transcriptional dysregulation, both decreased and increased, compared to controls, suggesting the potential for both loss- and gain-of-function mechanisms that could alter DNA binding specificity. The frameshift mutations were predicted to result in a loss of function either by triggering nonsense-mediated mRNA decay or by truncating the DNA-binding zinc finger domains. However, cellular studies of the frameshift mutations and studies of patient cells were not performed. Zebrafish with complete loss of zfx showed mild behavioral abnormalities in some assays, such as decreased anxiety behavior and poor habituation, compared to wildtype, although other behavioral assays were similar to wildtype (see ANIMAL MODEL). The authors suggested that truncating mutations resulting in a loss of zfx function may result in neurocognitive abnormalities.

Shepherdson et al. (2024) found that CRISPR/Cas9-mediated knockdown of the zfx gene in zebrafish did not result in morphologic developmental abnormalities. Mutant zebrafish showed some behavioral abnormalities compared to wildtype, including decreased anxiety behavior in the novel tank diving and scototaxis assays. Mutant fish also did not habituate in the external tap assay compared to wildtype. Social interaction and mirror biting tests were similar in mutants and controls. These findings suggested to the authors that a loss of zfx function may result in subtle neurocognitive abnormalities.