Karlien Mul, Richard J L F Lemmers, Marjolein Kriek, Patrick J van der Vliet, Marlinde L van den Boogaard, Umesh A Badrising, John M Graham, Angela E Lin, Harrison Brand, Steven A Moore, Katherine Johnson, Teresinha Evangelista, Ana Töpf, Volker Straub, Solange Kapetanovic García, Sabrina Sacconi, Rabi Tawil, Stephen J Tapscott, Nicol C Voermans, Baziel G M van Engelen, Corinne G C Horlings, Natalie D Shaw, Silvère M van der Maarel

To determine whether congenital arhinia/Bosma arhinia microphthalmia syndrome (BAMS) and facioscapulohumeral muscular dystrophy type 2 (FSHD2), 2 seemingly unrelated disorders both caused by heterozygous pathogenic missense variants in the SMCHD1 gene, might represent different ends of a broad single phenotypic spectrum associated with SMCHD1 dysfunction. We examined and/or interviewed 14 patients with FSHD2 and 4 unaffected family members with N-terminal SMCHD1 pathogenic missense variants to identify BAMS subphenotypes. None of the patients with FSHD2 or family members demonstrated any congenital defects or dysmorphic features commonly found in patients with BAMS. One patient became anosmic after nasal surgery and one patient was hyposmic; one man was infertile (unknown cause) but reported normal pubertal development. These data suggest that arhinia/BAMS and FSHD2 do not represent one phenotypic spectrum and that SMCHD1 pathogenic variants by themselves are insufficient to cause either of the 2 disorders. More likely, both arhinia/BAMS and FSHD2 are caused by complex oligogenic or multifactorial mechanisms that only partially overlap at the level of SMCHD1.