Ichthyosis Follicularis, Alopecia, and Photophobia (IFAP) Syndrome via the MBTPS2 Gene

Intellectual Disability (ID) is a heterogeneous group of neurodevelopmental disorders, characterized by congenital limitation in intellectual functioning (intelligence quotient, IQ ≤70), and adaptive behavior. It is diagnosed in ~1–3% of the population before 18 years of age (American Association of Intellectual and Developmental Disabilities, AAIDD). X-linked Intellectual Disability (XLID) contributes almost 10-15% of intellectual disability (ID) cases in males.

Deficiency of Membrane-Bound Transcription Factor Site-2 Protease (MBTPS2) leads to X-linked Ichthyosis Follicularis, Alopecia, and Photophobia (IFAP) syndrome (with or without BRESHECK syndrome). IFAP syndrome is a multiple congenital malformation disorder and is associated with impaired cholesterol homeostasis and endoplasmic reticulum stress response (Oeffner et al. 2009. PubMed ID: 19361614). Clinical features of IFAP widely vary and may include (but may not be limited to) delayed psychomotor development, motor delay, speech delay, intellectual disability, seizures, brain malformations, microcephaly, short stature, breathing difficulties, inguinal hernia, hearing loss, visceral and skeletal malformations, joint hyper extensibility, dysmorphic facies (eyelid ptosis, cleft palate, large prominent nose, short philtrum, large dysplastic ears), and abnormalities of the skin, nails, hair, chest, ocular, gastrointestinal and genitourinary systems that include ichthyosis follicularis, noncicatricial and nonprogressive alopecia, photophobia and nail dystrophy (Tang et al. 2011. PubMed ID: 21315478, Pietrzak et al. 2012. PubMed ID: 22781927, Izumi et al. 2013. PubMed ID: 23551428, Zhang et al. 2016. PubMed ID: 27663151). Of note, early childhood deaths (within first ~2 years of life) have been reported in severely affected males (Izumi et al. 2013. PubMed ID: 23551428). Carrier females often manifest variable milder abnormalities of the skin, nails and hair, including patchy hair loss, sparse scalp hair, baldness, dry skin, hyperkeratotic plaques, nail dystrophy, linear scalp alopecia, brown scaly plaques, linear atrophy and scaling on the arm, shoulder, waist and legs (Pietrzak et al. 2012. PubMed ID: 22781927).

Interestingly, normal intelligence has also been reported among affected males harboring pathogenic MBTPS2 variants (Oeffner et al. 2009. PubMed ID: 19361614, Aten et al. 2010. PubMed ID: 20672378, Haghighi et al. 2013. PubMed ID: 22931912, Fong et al. 2015. PubMed ID: 25683132, Lindert et al. 2016. PubMed ID: 27380894). Based on a genotype-phenotype correlation study on the pathogenic MBTPS2 variants in male patients with IFAP, pathogenic variants primarily in the transmembrane domains 6–8 were found to be associated with severe phenotypes (Bornholdt et al. 2013. PubMed ID: 23316014). However, since phenotypic heterogeneity has been observed with the same MBTPS2 variant, the role of epigenetic alterations, modifier genes and ethnic background in the phenotypic heterogeneity of IFAP cannot be ruled out (Zhang et al. 2016. PubMed ID: 27663151).

IFAP syndrome is an X-linked disorder, caused by pathogenic variants in MBTPS2. MBTPS2 consists of 11 coding exons and maps to chromosome Xp22.12, encoding a 519 amino acid polypeptide. Membrane-Bound Transcription Factor Site-2 Protease (MBTPS2) is a transmembrane zinc metalloprotease essential for intramembrane proteolysis of sterol-regulatory element-binding proteins (Pietrzak et al. 2012. PubMed ID: 22781927). MBTPS2 functions in the control of cholesterol homeostasis and the ER stress response and has significant implication in development (Zhang et al. 2016. PubMed ID: 27663151). To date, only missense and splice site pathogenic variants have been reported (Human Gene Mutation Database). The disease transmission pattern is primarily X-linked recessive.

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 800 genes have been identified in individuals with ID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016. PubMed ID: 26503795). We expect the analytical sensitivity of the MBTPS2 single nucleotide variants to be high.

To date, no gross deletion or duplication involving MBTPS2 has been reported (Human Gene Mutation database).

This test provides full coverage of all coding exons of the MBTPS2 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).