X-linked Intellectual Disability (Turner Type) via the HUWE1 Gene

HUWE1-related XLID affects both males and females. Affected individuals have moderate to profound intellectual disability (100%), global developmental delay (95%), delayed speech and language development (89%), hypotonia (70%), short stature (70%), microcephaly (52%), brachydactyly (57%) and eye problems including blepharophimosis (57%), strabismus (65%), and refraction errors (50%). A majority of patients learn to walk within the first four years, however most remain nonverbal throughout their lifetime. Growth delays are often postnatal in onset. Patients do not have a recognizable facial gestalt, yet common facial characteristics include high forehead, long face, deep-set eyes, hypo or hypertelorism, epicanthal folds, broad nasal tip, thin upper lip, and low-set posteriorly rotated ears (Moortgat et al. 2018. PubMed ID: 29180823). Additional common features include seizures, autistic traits, hearing loss, MRI abnormalities, contractures, overlapping toes, hyperactivity, sleep difficulties, and stereotypies. More rarely, feeding difficulties, scoliosis, craniosynostosis, hypertonicity, constipation, hyperpilosity, and cryptorchidism have been observed. Affected females range widely in disease severity, which is predicted to be due to skewed X-inactivation patterns, perhaps even acting in a tissue-specific manner (Moortgat et al. 2018. PubMed ID: 29180823).

While there is no treatment for this disorder, advantages of testing may include prognostic information, early identification and treatment of symptoms such as growth delay, eye problems, seizures, and autism, and ability to join HUWE1 family support groups. For families with inherited causative variants, prenatal testing or pre-implantation genetic diagnosis may be implemented for future pregnancies. Alternatively, a confirmed de novo variant (implicating lower recurrence risk), may ease anxiety for reproductive planning.

Literature evidence supports both X-linked dominant and X-linked recessive inheritance patterns for HUWE1-associated XLID. Most affected females carry de novo variants. Affected males can have hemizygous de novo variants, or inherit a pathogenic variant from an unaffected or mildly affected mother. Evidence suggests that X-inactivation skewing in females can affect the penetrance and severity of the disease, therefore X-inactivation studies of females may be helpful when assessing the significance of a HUWE1 variant during family segregation studies (Moortgat et al. 2018. PubMed ID: 29180823; Muthusamy et al. 2019. PubMed ID: 30797980).

The majority of pathogenic HUWE1 variants are missense alterations, which are widely spread throughout the gene. Some enrichment of pathogenic variation is seen in the protein's functional domains, particularly the large HECT domain at the end of the protein. The second most common variant type is large duplications, typically encompassing the entire gene, and sometimes additional genes. Other variant types exist in small numbers, including canonical splice alterations and large deletions. Notably, frameshift and nonsense variants are extremely rare in the literature and public databases, suggesting that a majority of HUWE1 loss of function alterations may be lethal in humans.

HUWE1 is located at Xp11.22, consists of 84 exons, and codes for a 4374 amino acid protein (Ensembl). HUWE1 stands for HECT, UBA, and WWE Domain-containing protein 1 (Uniprot). It is an E3 ubiquitin-protein ligase, with defined roles in many stages of neuronal development, and is essential for survival in mice (Zhao et al. 2009. PubMed ID: 19686682; D'Arca et al. 2010. PubMed ID: 20231446).

Pathogenic variants in HUWE1 are expected to account for <0.1% of cases of intellectual disability (ID), and less than 2% of individuals with X-linked ID (XLID). In this context, it is important to note that pathogenic variants in over 140 genes have been associated with XLID (Neri et al. 2018. PubMed ID: 29696803). Testing a large panel of genes as well as using a trio approach (testing parents) is known to have higher diagnostic yield due to the extreme clinical and genetic heterogeneity of intellectual disability (Vissers et al. 2016. PubMed ID: 26503795).

Single nucleotide variants (SNVs) are the most common type of variant known to cause HUWE1-related XLID (Human Gene Mutation Database), therefore analytical sensitivity for HUWE1 SNVs is expected to be very high. Large duplications of HUWE1 are another common cause of HUWE1-associated XLID (Froyen et al. 2008. PubMed ID: 18252223; Froyen et al. 2012. PubMed ID: 22840365). The reported duplications are large, with a majority including the entire gene. Analytical sensitivity using our NGS-CNV detection method is expected to be close to 100% for this type of large duplication. In summary, this test is expected to detect nearly all clinically relevant variants in HUWE1.

This test provides full coverage of all coding exons of the HUWE1 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).