CCDC47 gene and trichohepatoneurodevelopmental syndrome: Report of the fifth and sixth cases from Saudi Arabia.

Trichohepatoneurodevelopmental syndrome (THNS) is an ultra-rare and complex disorder affecting multiple organ systems. It is characterized by liver dysfunction, hypotonia, global developmental delay, coarse hair, and dysmorphic features. We describe two cases of THNS of Saudi origin, the fifth and sixth cases in the medical literature. Both cases presented with multiple dysmorphic features, generalized hypotonia, global developmental delay, and high liver enzyme level. Exome sequencing of Case 1 identified a pathogenic homozygous variant within the CCDC47: NM_020198.2:c.567_570del, p.(Glu190Profs*7). Genome sequencing of Case 2 identified two likely pathogenic heterozygous variants within the CCDC47: NM_020198.2:c.1327C>T, p.(Arg443*) and NM_020198.2:c.422dup, p.(Leu141Phefs*19). The trans phase of the detected variants has been confirmed by the parental testing. Furthermore, we evaluated the gene-disease association as per ClinGen guidelines and reached a strong level of association after inclusion of the new patients/variants. The findings from these cases will help to delineate the clinical phenotype and the mutational spectrum of this complex disorder.

Adding to the evidence of gene-disease association of RAP1B and syndromic thrombocytopenia.

Syndromic constitutive thrombocytopenia encompasses a heterogeneous group of disorders characterised by quantitative and qualitative defects of platelets while featuring other malformations. Recently, heterozygous, de novo variants in RAP1B were reported in three cases of syndromic thrombocytopenia. Here, we report two additional, unrelated individuals identified retrospectively in our data repository with heterozygous variants in RAP1B: NM_001010942.2(RAP1B):c.35G>A, p.(Gly12Glu) (de novo) and NM_001010942.2(RAP1B):c.178G>A, p.(Gly60Arg). Both individuals had thrombocytopenia, as well as congenital malformations, and neurological, behavioural, and dysmorphic features, in line with previous reports. Our data supports the causal role of monoallelic RAP1B variants that disrupt RAP1B GTPase activity in syndromic congenital thrombocytopenia.