Novel compound heterozygous variants in the LARP7 gene in a patient with Alazami syndrome

Abstract

The LARP7 gene encodes a chaperone protein of the noncoding RNA 75 K, and mutations in this gene have been identified in patients with Alazami syndrome. Herein, we report another Japanese patient with Alazami syndrome and novel compound heterozygous variants in LARP7 (i.e., c.370delG, p.Glu124fs*38 and c.641_667+25del involving the splice donor site of intron 8). These findings provide further evidence that biallelic LARP7 defects cause the phenotype of Alazami syndrome.

Alazami syndrome in an Afghani girl: A case report and review of literature

“…The mutational mechanism is loss-of-function presumably due tononsense-mediated mRNA decay [1,5] [3,5]. Our patient's fi nal adult height is not as signifi cantly impaired as the initial case descriptions [2,3,6] and not in the range typical for primordial dwarfi sm, and more in accordance with the growth reported byHollink et al, [1] and Dateki et al [5].…”

“…Hollink et al, [1], reported two unrelated Alazami syndrome patients with homozygous loss-of-function variants in LARP7. Dateki et al, [5], reported another patient with Alazami syndrome having unique compound heterozygous mutations in LARP7 [5]. Recently Imbert-Bouteille M et al, [6], with other previously reported Alazami syndrome patients to portray further phenotypic manifestations related to this syndrome.…”

“…Okamura et al, [9], identifi ed gene-specifi c as well as celltype-specifi c transcription activation in mouse embryos due to 7SK snRNP mediated regulation of P-TEFb activity, thus proposing LARP-7 mediated transcription regulation incites cell cycle progression in actively proliferating primordial germ cells (PGCs), which proliferate excessively in early mammalian embryos. In addition, Dai et al, [10], determined that knockdown of LARP 7 downregulatesLin28, a positive regulator of organismal growth, causing premature differentiation of embryonic stem cells, resulting in growth defi ciency.All cases of Alazami syndrome have been due to homozygous or compound heterozygous frameshift variants in LARP7[1][2][3][4][5][6].…”

Updating the neurodevelopmental profile of Alazami syndrome: Illustrating the role of developmental assessment in rare genetic disorders

“…We describe a male infant who, at 17 months of age, is the youngest patient diagnosed with Alazami syndrome to date. He is also the first reported patient with an intronic variant predicted to cause abnormal splicing, as the variants previously‐reported in the literature are frameshift variants resulting in a prematurely truncated protein (Alazami et al, ; Dateki et al, ; Hollink et al, ; Holohan et al, ; Imbert‐Bouteille et al, ; Ling & Sorrentino, ). His physical development appears consistent with previous reports of Alazami syndrome, with short stature and characteristic facial features noted in addition to other features particular to Alazami syndrome such as overlapping toes and rough skin over his feet.…”

“…In fact, only one patient is reported to have meaningful speech (Hollink et al, ), though these details are not consistently provided, and the younger patients reported may have yet to develop additional language skills. These individuals also share a unique facial gestalt with the initial family described and are all reported to have pathogenic protein‐truncating variants in LARP7 (Dateki et al, ; Hollink et al, ; Holohan et al, ; Imbert‐Bouteille et al, ; Ling & Sorrentino, ). The age at diagnosis ranges from 2 to 26 years of age and many families are reported to be consanguineous (Dateki et al, ; Hollink et al, ; Holohan et al, ; Imbert‐Bouteille et al, ; Ling & Sorrentino, ).…”