HCFC1-Related Disorders via the HCFC1 Gene

Defects in the HCFC1 gene have been reported to be causative for both X-linked intellectual disability type 3 (XLID 3) and combined methylmalonic aciduria and homocystinuria, cblX type (Huang et al. 2012; Yu et al. 2013; Jolly et al. 2015).

In the reported XLID 3 patients, most were classified as having mild-to-moderate intellectual disability, though a few have been reported with severe intellectual disability. Other commonly reported features include behavioral problems such as aggression or hyperactivity, anxiety, and autistic features. Some of the patients have been reported to present with microcephaly and facial dysmorphism (Huang et al. 2012; Jolly et al. 2015; Koufaris et al. 2016).

Patients diagnosed with the cblX disorder have mainly presented during early infancy with severe developmental delays, intractable epilepsy, and failure to thrive. Other clinical features that have been observed include hypotonia, brain abnormalities, microcephaly, ketoacidosis, hyperammonemia, choreoathetosis, and multiple congenital anomalies that may include genital abnormalities. Biochemically, the cblX patients also have signs of combined methylmalonic aciduria and homocystinuria, including increased methylmalonic acid in the serum and/or urine, increased total homocysteine levels, and decreased methionine (Yu et al. 2013; Gérard et al. 2015; Jolly et al. 2015; Niranjan et al. 2015). The cblX form of HCFC1 deficiency tends to be more severe than the XLID type 3 form (Jolly et al. 2015).

Combined methylmalonic aciduria and homocystinuria can also be caused by defects in the MMACHC, MMADHC, ABCD4 and LMBRD1 genes (Carrillo-Carrasco et al. 2013). Though cellular complementation studies can typically pinpoint the specific form of cobalamin deficiency in a patient, the genetic cause of a number of cblC type methylmalonic aciduria and homocystinuria cases (MMACHC deficiency) has not been found (Yu et al. 2013). Recent studies have shown that pathogenic variants in the HCFC1 gene can explain a large percentage of these cases (Yu et al. 2013).

XLID type 3 and methylmalonic aciduria and homocystinuria cblX type are caused by pathogenic variants in HCFC1, which is located on the X chromosome. These disorders are inherited in an X-linked recessive fashion (Huang et al. 2012; Yu et al. 2013). Thus far, all affected individuals that have been reported have been male. Variants may be inherited or arise de novo (Huang et al. 2012; Yu et al. 2013). To date, more than 10 pathogenic variants have been reported in the HCFC1 gene. With the exception of one regulatory variant found in a large XLID type 3 family, most variants have been missense (Human Gene Mutation Database). The most commonly reported variant is c.218C>T (p.Ala73Val), which was reported in nine cblX patients (Yu et al. 2013). There does appear to be a genotype-phenotype correlation, with loss-of-function variants being associated with the more severe cblX presentation and partial loss-of-function variants being associated with XLID type 3 (Jolly et al. 2015). The severity also seems to be dependent upon location within the protein. Thus far, nearly all variants that have been linked with the cblX presentation have been located in the Kelch domain region of the protein or within the nuclear localization signal sequence (Yu et al. 2013; Gérard et al. 2015; Jolly et al. 2015; Niranjan et al. 2015). Variants associated with XLID have been found in other locations within the HCFC1 protein (Huang et al. 2012; Jolly et al. 2015; Koufaris et al. 2016).

The HCFC1 gene encodes a transcriptional co-regulator protein that has been shown to play a role in regulating the expression of the MMACHC gene, in addition to many other genes involved in cellular proliferation and other critical functions (Jolly et al. 2015). Both MMACHC and HCFC1 defects lead to neurological impairment, though HCFC1 deficiency tends to be more severe. It is believed that this is because the HCFC1 protein is involved in the regulation of many other genes in addition to MMACHC (Jolly et al. 2015).

Clinical sensitivity of this test should be high in patients with HCFC1 deficiency. For example, Yu and colleagues (2013) reported pathogenic variants in 13 out of 17 male patients who were suspected of or cellularly diagnosed with cblc type methylmalonic aciduria and homocystinuria but did not harbor pathogenic variants in the MMACHC gene. The clinical sensitivity of HCFC1 testing in patients suspected of X-linked intellectual disability (XLID) is more difficult to predict, given that ~0.15-0.3% of the population is predicted to be affected with this disorder (Koufaris et al. 2016), and HCFC1 variants would be expected explain only a subset of those cases. Analytical sensitivity of this test is expected to be high as all variants reported to date should be detectable via sequencing.

This test provides full coverage of all coding exons of the HCFC1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other 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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

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).