MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive c erebellar, o cular, cranio f acial and g enital features (COFG syndrome)

Abstract

Background: Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs.

Objective: A homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families.

Results: We identified four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly.

Conclusion: This report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis.

Keywords: MAB21L1; Cerebello-Oculo-Facio-genital (COFG) syndrome; corneal dystrophy; pontocerebellar hypoplasia; scrotal/labial aplasia.

Figure 1

Clinical phenotype of COFG individuals harbouring biallelic MAB21L1 loss of function variants. (A–L) Depicted craniofacial dysmorphism, medially sparse/flared and laterally extending eyebrows, synophrys, buphthalmos, anteverted nares, long and tented philtrum, flat nasal bridge, low anterior hairline and horizontal nystagmus with strabismus (A–D: individuals from family 1; E–H and Aa: individual 4_V:1 from 7 years of age to adulthood; I, J, Ab: individual 5_IV:1 from childhood to adulthood; K, L: individual 4_IV.4 from childhood to adulthood, M: individual 3_II.3). Widely spaced hypoplastic nipples with no noticeable areolae or hyperpigmentation and a tuft of terminal hair extruding from the lactiferous ducts (N: individual 1_VI:7; O: individual 4_V:1; P: 5_IV:4). Undescended testes, bilateral scrotal agenesis with normal median raphe in individual 1_VI:2 (Q), 4_V:1 (R), 5_IV:4 (S). Absence of labia majora and small labia minora in individuals 1_VI:5 (T) and 5_IV:1 (U). Corneal opacities in individual 1_VI:7 (V) and individual 5_IV:1. (V`). Cerebellar hypoplasia with absence/hypoplasia of the vermis in individuals 2_II:3 (W, X), 4_V:1 (Z, I_IV.V). Optic atrophy in individual 2_II:3 (Y). COFG, Cerebello-Oculo-Facio-Genital.

Figure 2

Pedigrees, MAB21L1 mutation segregation patterns and mutation localisation on cDNA and protein level. (A) Pedigrees of four families harbouring biallelic MAB21L1 loss-of function variants identified by ES. In total, nine affected individuals were identified. Wildtype alleles are indicated by ‘+’, alleles carrying identified variants with ‘ -’. (B) Visualisation of the MAB21L1 gene and COFG associated alleles identified by us as well as the previously identified MAB21L1 allele Bruel et al. (C) Schematic overview of localisations of COFG alleles on protein level. (D) Computational structural model of human MAB21L1, Visualisation of the aminoacid change identified in family 2 and predicted effect on protein folding/structure and evolutionary conservation of the mutated position among species. The variant is predicted to disrupt hydrogen bond formation within the alpha-helix structure, disrupting the protein secondary structure. COFG, Cerebello-Oculo-Facio-Genital; ES, exomic sequencing.