Exploring the phenotypic spectrum and osteopenia mechanisms in Yunis-Varón syndrome

Abstract

Purpose: Biallelic variants in FIG4 or VAC14 are associated with Yunis-Varón syndrome (YVS), which is characterized by multisystem involvement including skeletal findings, craniofacial dysmorphisms and central nervous system anomalies. Pathogenic variants in those same genes have also been associated with a predominantly neurological phenotype and with nonsyndromic conditions, such as Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. By describing 5 new cases of FIG4-associated YVS and reviewing the literature, we better delineate the clinical phenotype associated with loss of function of those genes. We also explore osteopenia mechanisms by assessing bone physiologic parameters in a mouse model.

Methods: Exome sequencing or Sanger sequencing was performed in 5 unrelated individuals. Bone histomorphometry was performed in Fig4 ^plt/plt mice and compared with wild type. Relevant literature from the last 10 years was reviewed.

Results: All individuals presented a phenotype overlapping the typical YVS and the brain anomalies and neurologic syndrome. Clinical features included developmental delay, structural brain malformations, and skeletal anomalies, such as osteopenia. Biallelic FIG4 variants were identified in each individual. In mice, bone histomorphometry parameters suggested that osteopenia might be secondary to reduced bone formation rather than increased bone degradation.

Conclusion: This study contributes to a better understanding of the phenotypic variability caused by pathogenic variants in FIG4 or VAC14 and suggests an important overlap between previously described phenotypes. The brain anomalies and neurologic syndrome is likely in the same spectrum as classical YVS. Further studies are still needed to clarify the effects of partial loss-of-function (hypomorphic) variants and to identify genotype-phenotype correlations.

Keywords: Exome sequencing; FIG4; Osteopenia; VAC14; Yunis-Varón syndrome.

Figure 1

Photographs, brain imaging and X-rays of affected individuals. A. Individual 4. Note microcephaly, sparse scalp hair, absent eyebrows and eye lashes, protruding eyes, anteverted nares, short philtrum, micrognathia, low-set dysplastic ears with brachydactyly, thumb and hallux hypoplasia, and hypoplastic nails. B-D. Brain imaging of individual 3. B. CT axial: diffuse pachygyria with ventricular dilatation more significant at the left ventricle. C. MRI axial T2: frontal bilateral pachygyria, extreme bilateral ventricular dilatation, IV ventricle dilatation, thinned mesencephalus, atrophic cerebellum, and thinned thalamus. D. MRI sagittal T1: “J-shaped” sella, thinned cerebral cortical parenchyma and Dandy-Walker malformation. E and F. Skull X-ray, frontal and lateral plane of individuals from family 3 (E) and family 4 (F). Note unmineralized skull and craniofacial disproportion. G. Chest Radiograph showing narrow chest and hypoplastic clavicles in individual from family 4. H. Plain abdominal X-ray showing pelvic dysplasia in individual from family 4. I. Upper limb X-ray of individual 4 showing complete absence of thumb, hypoplasia of halluces, and hypoplastic middle and distal phalanges.

Figure 2

Segregation of FIG4 variants in 5 families and location of FIG4 variants. A. FIG4 genotypes of family members demonstrating autosomal recessive inheritance. Numbering from RefSeq NM_014845.5. B. Location of variants in FIG4 exons; introns not drawn to scale. Above, YVS; below, Brain anomalies and neurologic syndrome. Phosphoinositide polyphosphatase domain, green; Sac1 homology domain-containing inositol phosphatase, purple; P loop containing the catalytic CX5R(T/S) motif, orange. Arrows point to FIG4 variants reported in this study. C. Evolutionary conservation of amino acids around the missense variants. Dots represent identity.

Figure 3

Bone Physiologic Parameters and Abnormal Subcellular Morphology in FIG4 mutated fibroblasts. A. Von Kossa and Goldner staining of lumbar vertebrae in Fig4^plt/plt and Fig4^+/+ mice. B. Vertebral bone parameters. S/V, surface/volume; V/V, volume/volume; Tb.N, trabecular number; ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. C. Tartrate-resistant acid phosphatase staining in Fig4^+/+ and Fig4^plt/plt mice. Oc.S/BS, osteoclast surface/bone surface; N. Oc, osteoclast number. D. Double calcein staining in Fig4^+/+ and Fig4^plt/plt mice. E. Mineralization application rate (MAR), mineralized surface (MS/BS) and bone formation rate (BFR). ∗P < .05. F. Light microscopy of cultured skin fibroblasts from individual 1 showing large, empty cytoplasmic vacuoles.