Patient TTD218UT is of Moroccan origin and was born to consanguineous parents. She was referred to the clinical geneticist at 1.5 years of age with brittle hair (low cysteine content and tiger-tail banding pattern), ichthyosis, microcephaly (−2.5 SD), psychomotor retardation, short stature (−2.5 SD) and microcytic anemia. She showed recurrent aggravation of hair-loss by tufted breakage at the scalp boundary immediately following episodes of infection-induced fever. Also upon long-term exposure to the heat of the sun, she appears to have increased hair-loss. At the age of 8 years, she shows no signs of progressive deterioration. She has a happy and friendly personality with an IQ of 54 (at 7 years of age). She has a limited physical endurance. Laboratory investigation revealed microcytic hypochromic anemia (Hb 6.5) without sequence anomalies nor deletions or duplications of the genes encoding for the alpha or beta globin chains (not shown). We performed whole genome sequencing on patient’s DNA, using the sequencing-by-ligation method from Complete Genomics (16,17). Surprisingly, we identified a homozygous variant in the GTF2E2/TFIIEβ gene, creating a missense mutation (c.C559T [p.Asp187Tyr]). This mutation is identical to one of the mutations in GTF2E2/TFIIEβ previously described by Kuschal et al. (14). Its homozygous presence was confirmed by Sanger sequencing of cDNA generated from patient’s cells and found to co-segregate with the phenotype within the family (Fig. 1A and B).
Case: TTD218UT
Demographics: Female, 1.5 years at diagnosis. Moroccan origin.
CasePresentingHPOs: HP:0004779, HP:0045055, HP:0008064, HP:0000252, HP:0001263, HP:0004322, HP:0001935, HP:0004840, HP:0040082, HP:0100025
Individual showed recurrent aggravation of hair-loss by tufted breakage at the scalp boundary immediately following episodes of infection-induced fever, and upon long-term exposure to the heat of the sun, she appears to have increased hair-loss. She had an IQ of 54 (at 7 years) and limited physical endurance.
CaseNOTHPOs: Progressive deterioration at 8 years
CasePreviousTesting: None
CaseGenotypingMethod: Whole genome sequencing, confirmed by Sanger sequencing.
Variant: NM_002095.5(GTF2E2):c.C559T [p.Asp187Tyr]
ClinVar ID: 225841
Pathogenic, non-LOF variant gnomAD: hypomorphic, homozygous missense. Not in gnomAD.
AddCaseInfo: The parents of this individual were consanguineous and were heterozygous for the mutation. Of 3 siblings, two (a brother and a sister) were found to be heterozygous carriers, while one was found to have the homozygous wild type alleles (a sister).
VariantEvidence: The variant has been previously reported by Kauschal et al (26996949) in a 16-yr old Moroccan girl. The identification of this variant in four individuals of Moroccan origin suggests the possibility of a founder mutation. Since the variant has been already scored, this proband is not being scored.