Genetic Testing and Molecular Biomarkers

Intellectual Disability-Obesity-Brain Malformations-Facial Dysmorphism Syndrome (IDOB-FMD) is a rare genetic disorder characterized by moderate to severe intellectual disability, microcephaly, and brain abnormalities such as a thin corpus callosum, cerebellar hypoplasia, and cerebral white matter hypoplasia, often observed on MRI scans. Additional features include obesity and craniofacial dysmorphism. IDOB-FMD is inherited in an autosomal recessive manner, attributed to Trafficking Protein Particle Complex Subunit 9 (TRAPPC9) deficiency, with a prevalence of less than 1 in 1,000,000. This syndrome shares clinical similarities with Prader–Willi syndrome (PWS).

In our study, we conducted a clinical evaluation of two Tunisian siblings suspected of having Prader–Willi-like syndrome (PWLS) based on their clinical presentation. Whole-exome sequencing (WES) was employed to identify genetic variants associated with the phenotype. Variant interpretation and segregation analysis were performed to ascertain the pathogenicity of the identified variants. WES revealed a homozygous mutation in the TRAPPC9 gene in both siblings. The variant was predicted to be pathogenic and segregated with the phenotype within the family. Clinical examination was consistent with PWLS, including intellectual disability, microcephaly, and dysmorphism.

Our findings emphasize the importance of genetic testing in patients presenting with PWLS features, highlighting a TRAPPC9 mutation that expands the known mutational spectrum. This study, the second investigation of PWLS in Tunisia, reports a pathogenic variant in the TRAPPC9 gene underlying the observed phenotype in this family, offering valuable insights into clinical management and genetic counseling. Our identification of this variant not only reveals genetic heterogeneity but also prompts further research to elucidate the genotype-phenotype correlations and molecular mechanisms underlying TRAPPC9-related disorders.

We estimated European ancestry in U.S. Hispanics using HFE p.C282Y (c.845G > A; rs1800562), a highly informative autosomal marker of European ancestry.

We tabulated published p.C282Y allele frequencies in U.S. Hispanic control/population region/city cohorts. We assumed that Hispanics inherited p.C282Y from European ancestors only. We defined European ancestry (M) of each cohort as the quotient of its published p.C282Y frequency by the published aggregate p.C282Y frequency in Iberian Spaniards. We compared the present average region/city values of M and the aggregate M with previous European ancestries of U.S. Hispanics estimated using multiple ancestry-informative markers (AIMs).

There were 14,472 Hispanics (nine region/city cohorts; aggregate p.C282Y frequency 0.0176 [509/28,944] [95% confidence interval: 0.0159, 0.0189]). There were 12,297 Spaniards (34 population/control cohorts; aggregate p.C282Y frequency 0.0291 (716/24,594) [0.0271, 0.0313]). Nine region/city estimates of M differed 2.6-fold: Alabama 1.0000, California/Irvine 0.5395, California/Oakland 0.6186; California/San Diego 0.9381; Connecticut 0.6873; District of Columbia 0.3883; Hawaii 0.6976; New York 0.4330; and Oregon 1.0000. The average of these nine region/city estimates of M was 0.7003. The aggregate estimate of M in the present 14,472 Hispanics was 0.6048 [0.5369, 0.6728]. The range of estimated European ancestries in 29,365 Hispanics in eight previous studies that used multiple AIMs was 0.502–0.683.

European ancestry in U.S. Hispanics estimated using p.C282Y frequencies varies across regions/cities. The average nine region/city and aggregate European ancestry estimates in the present U.S. Hispanics are similar to those in eight previous studies that used multiple AIMs.