Alazami Syndrome

A number sign (#) is used with this entry because of evidence that Alazami syndrome (ALAZS) is caused by homozygous or compound heterozygous mutation in the LARP7 gene (612026), a chaperone of 7SK noncoding RNA (616505), on chromosome 4q25.

Description

Alazami syndrome is an autosomal recessive disorder characterized by severe growth restriction present at birth, severely impaired intellectual development, and distinctive facial features. Some patients have been reported with skeletal and behavioral features (summary by Imbert-Bouteille et al., 2019).

Clinical Features

Alazami et al. (2012) described a large consanguineous family from the Southern Province in Saudi Arabia in which 10 children among 3 interrelated branches had facial dysmorphism, severely impaired intellectual development, and primordial dwarfism. All patients had growth parameters 3.5 SD below the mean. Some patients had nonspecific and inconsistent skeletal findings, for example, scoliosis and mild epiphyseal changes in the proximal phalanges, but no frank dysplasia and a bone age consistent with chronological age. Consistent dysmorphic features included malar hypoplasia, deep-set eyes, broad nose, short philtrum, and macrostomia. Laboratory investigation revealed normal plasma amino acids and acylcarnitines, urine organic acids, very long-chain fatty acids, CBC, renal profile, and bone profile. MRI, which was performed on 2 patients, was largely unremarkable in one and showed unilateral mild insular and anterior frontal gyrus cortical thickening in the other.

Ling and Sorrentino (2016) reported a 2-year-old Caucasian girl, born of unrelated parents, with Alazami syndrome. She had failure to thrive, poor overall growth, short stature (-4 SD), and developmental delay with involuntary hand movements and poor speech. Dysmorphic features included 'small-appearing' head, prominent forehead, deep-set eyes, low-set ears, flat and wide nasal bridge, triangular facies with malar hypoplasia, wide mouth, full lips, and widely spaced teeth. She also had poor balance with wide-based gait and hypersensitivity to touch and sound, and she reportedly showed anxiety. Brain imaging was normal.

Imbert-Bouteille et al. (2019) reported 2 sisters, born to consanguineous Algerian parents, with Alazami syndrome. The authors reviewed the clinical information on 15 previously reported patients in addition to their 2 newly reported patients and confirmed the key features of the syndrome: severe growth restriction, severely impaired intellectual development, and distinguishing facial features, including broad nose, malar hypoplasia, wide mouth, full lips, and widely spaced teeth. They also noted that most patients (11/14) had disproportionately mild microcephaly (with height more severely affected than head circumference) and that some patients had thickened skin over the hands and feet (11/14), stereotypic hand wringing (2/5), severe anxiety (2/5), and scoliosis (4/13).

Mapping

Alazami et al. (2012) performed genomewide linkage analysis on 6 affected sibs from a large consanguineous Saudi family segregating a syndrome of facial dysmorphism, intellectual disability, and primordial dwarfism, and identified a 26.5-Mb autozygous region between SNPs (rs13142562 and rs2391504) on chromosome 4q24-q28.2 (maximum multipoint lod score of 4.456).

Molecular Genetics

By sequencing the LARP7 gene within the critical region of 4q identified for a syndrome of facial dysmorphism, intellectual disability, and primordial dwarfism in a consanguineous Saudi family, Alazami et al. (2012) identified a homozygous 7-bp duplication in exon 8 (612026.0001), which fully segregated with the disorder. The mutation was not found in 188 unrelated Saudi controls, a local database of 194 exomes, or the 1000 Genomes Project database. Western blot analysis revealed complete lack of LARP7 on patient cell lysates, and real-time PCR demonstrated reduced LARP7 expression in patient cells, compared to those of healthy controls, in both lymphoblast and fibroblast tissues, suggesting that total loss of the protein was due to nonsense-mediated decay. Concurrent with this was a profound reduction of the 7SK ncRNA. By introducing a LARP7 expression vector, Alazami et al. (2012) rescued 7SK levels in patient fibroblasts. Conversely, siRNA-mediated knockdown using 2 different oligos directed at LARP7 mRNA resulted in ablation of 7SK levels in healthy fibroblast cells.

In 2 affected members of a consanguineous Iranian family segregating severe intellectual disability and microcephaly, Najmabadi et al. (2011) had identified an 'apparently disease-causing' homozygous mutation in the LARP7 gene (612026.0002). No other clinical information was provided.

In a 2-year-old Caucasian girl, born of unrelated parents, with Alazami syndrome, Ling and Sorrentino (2016) identified compound heterozygous frameshift mutations in the LARP7 gene (612026.0003 and 612026.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.

In 2 sisters, born to consanguineous Algerian parents, with Alazami syndrome, Imbert-Bouteille et al. (2019) identified a homozygous frameshift mutation in the LARP7 gene (612026.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the Exome Sequencing Project, 1000 Genomes Project, or gnomAD databases.