Alternative titles; symbolsMENTAL RETARDATION, SHORT STATURE, FACIAL ANOMALIES, AND JOINT DISLOCATIONS▼ Clinical FeaturesMegarbane and Cormier-Daire (2001) descr...
Alternative titles; symbols
▼ Clinical Features
Megarbane and Cormier-Daire (2001) described 2 Lebanese sisters, the offspring of first-cousin parents, with short stature, obesity, bulbous nasal tip, microretrognathia, brachydactyly, joint hyperlaxity and dislocations, and severe mental retardation. Radiologic abnormalities included widened mandibular angles, thin temporal processes, hypoplastic clavicles, short distal ends of ulnas, short fourth metacarpals, and dislocation of hips, elbows, and thumbs. Autosomal recessive inheritance was believed to be the most likely mode of inheritance.
Ansar et al. (2019) reported 5 affected individuals from a consanguineous Pakistani family (family F145) with global developmental delay, mildly to severely impaired intellectual development, delayed or slurred speech, and short stature. Dysmorphic features included a large bulbous nose and variable microretrognathia. Two patients had strabismus and 1 had microcephaly (-3.1 SD). Two patients had behavioral problems, including aggression or shyness. Detailed radiographic studies revealed no skeletal abnormalities, and none of the patients had a history of joint laxity or dislocations. Brain imaging in 1 patient was normal. Ansar et al. (2019) also reported a 23-year-old Italian man, born of distantly related parents (family M213), with global developmental delay, walking at 30 months, and speech delay with only short sentences and dysarthria at the time of school age. He had moderately impaired intellectual development (IQ of 48 at age 20 years). Additional features included short stature, large bulbous nose, ptosis, an 'odd' and shy personality, and a disturbed sleep/wake cycle. Skeletal anomalies were not reported. (The legend in figure 1 of the article by Ansar et al. (2019) incorrectly stated that the Italian man was from family M039; Ansar (2019) confirmed that the correct family is M213 as stated in the text and table 1.)
The transmission pattern of IDDSFAS in the families reported by Ansar et al. (2019) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
In affected members of 2 unrelated consanguineous families (F002 and F145) with IDDSFAS, Ansar et al. (2019) identified a homozygous frameshift or nonsense mutation in the FBXL3 gene (605653.0001 and 605653.0002). The 2 affected sisters in family F002, who were originally reported by Megarbane and Cormier-Daire (2001), also carried homozygous missense variants in 2 other genes, E10A in PPARD (600409) and E511G in LMO7 (604362), that segregated with the phenotype in the family, which included skeletal abnormalities; a role for these variants could not be excluded. An affected patient from a third unrelated family (M213) was homozygous for a missense mutation in FBXL3 (C358R; 605653.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all 3 families. Functional studies of the variants and studies of patient cells were not performed, but the truncating mutations were predicted to result in absence of the FBXL3 C-terminal LRR domain that interacts with CRY2 (603732), causing a loss-of-function effect. The missense mutation C358R affected the same residue as that in the mutant murine model 'after hours' (C358S); see ANIMAL MODEL. In addition to the main features of IDDSFAS, this patient had a disturbed sleep/wake cycle, suggesting involvement of the circadian rhythm system. (In figure 1 of the article by Ansar et al. (2019), the third patient was incorrectly stated to be from family M039; Ansar (2019) confirmed that this patient is from family M213, as stated in the text and table 1 of the article.)
▼ Animal Model
By screening mutagenized mice for alterations in rhythms of wheel-running activity, Godinho et al. (2007) identified a mutation in the Fbxl3 gene that they termed 'after hours' (Afh). The Afh mutation caused a cys358-to-ser (C358S) substitution in the leucine-rich region of the Fbxl3 protein and resulted in free-running rhythms of about 27 hours in homozygotes. In situ hybridization, immunohistochemistry, and Western blot analyses showed that Afh altered expression of the negative regulators of the circadian clock in the suprachiasmatic nucleus, Per1 (602260), Per2 (603426), and Cry1, as well as the positive regulator, Bmal1. Godinho et al. (2007) concluded that FBXL3 has a central role in mammalian circadian timekeeping.