Intellectual disability syndromic and non-syndromic
Gene: ALMS1

ALMS1 (ALMS1, centrosome and basal body associated protein)
EnsemblGeneIds (GRCh38): ENSG00000116127
EnsemblGeneIds (GRCh37): ENSG00000116127
OMIM: 606844, Gene2Phenotype
ALMS1 is in 21 panels

2 reviews

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Green List (high evidence)

Early developmental delay is well reported, and is due to a variety of reasons: include gene for completeness, particularly as testing is often performed early in the diagnostic trajectory.
Created: 6 Dec 2022, 7:51 a.m. | Last Modified: 6 Dec 2022, 7:51 a.m.

Panel Version: 0.5099

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Alstrom syndrome, MIM# 203800

Created: 6 Dec 2022, 7:51 a.m.
Last Modified: 6 Dec 2022, 7:51 a.m.
Panel version: 0.5099

Christa Whelan (Genomic Diagnostics)

Red List (low evidence)

Evidence for a causal role of ALMS1 in intellectual impairment has not been reported. Whole organism transcriptome analysis of zebrafish models of ALMS1 (Alstrom Syndrome) knockout and BBS1 (Bardet-Biedl Syndrome) knock-out offspring identified significant downregulation of genes in pathways relevant to visual system deficits and obesity in both disorders, consistent with those shared phenotypes. In contrast, neuronal pathways were significantly downregulated only in the BBS model but not in the Alstrom model. This may be consistent with absent or very mild cognitive impairment in Alstrom patients, contrasting with BBS, downregulation of the neuronal system may be a unique characteristic of BBS (PMID: 27142762).

Cases of Alstrom syndrome with reported intellectual disability are often associated with known consanguinity or unknown family history and/or have not examined other possible genetic causes for reported ID.
In an evaluation of 61 Turkish patients diagnosed with Alstrom syndrome, cognitive deficits and motor impairment was documented in half of the patients (32/61). These represented a range of developmental issues from severe to milder cognitive impairments, gross and fine motor delay, language delay, attention deficit disorder (ADD), and autistic spectrum behaviour. Of those 30 analysed for genetic mutations, 18 presented with some degree of cognitive impairment (array CGH to detect copy number variations had not been carried out on these patient’s DNA samples). However of the 61 patients examined, 22 kindreds (48%) were born to consanguineous marriages, and 23 were either non-consanguineous or the family history was not known. It was noted that in the Turkish population, the consanguinity rate is estimated to be between 20–25%. (25296579).
A separate reported case of 4 siblings with Alstrom syndrome and reported intellectual impairment, however parents were known second cousins and consanguinity ran within the extended family (17146208).
Another reported a large multi-generational family with a total of 8 cases (first cousins) diagnosed with Alstrom syndrome. They shared many common clinical features of Alstrom syndrome as well as mild to moderate mental disability. Although consanguinity is not evident in this family, consanguinity was widely prevalent a few generations back in their tribal region (31889847).

Normal mentation is listed as a clinical phenotype which helps to distinguish Alstrom Syndrome from Bardet-Biedl (MIM # 203800 & 18154657).

Marshall et al (2015) reported that if the WHO criteria for defining and assessing intellectual disabilities (ID) is applied, fewer than 10% of Alstrom Syndrome patients meet that criteria. The early changes in vision and hearing have tremendous impact on social development, delay of cognitive development is not a common feature of Alstrom syndrome, delay in early fine and gross motor developmental milestones is seen in ~27% of affected children. There can be early learning difficulties, delays in language, or in gross or fine motor milestones, which tend, in most case, to resolve as the child ages (PMID: 25846608).

Intellectual disability or cognitive impairment may be reported in cases with Alstrom syndrome due to the effects of vision impairment and hearing loss, causing developmental and motor delays rather than intellectual impairment (17940554, 18154657, 22043170).

The majority of Alstrom syndrome cases reported have neither intellectual impairment or developmental delays (PMID 2231654, 8418611, 8181924, 8556827, 9663233, 25864795) and other studies document cases with developmental delay rather than intellectual disability (PMID 8556827; 1 family, 8 cases and 11941369; 6 families, unrelated).
Created: 5 Dec 2022, 10:20 a.m. | Last Modified: 5 Dec 2022, 10:20 a.m.

Panel Version: 0.5079

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Alström Syndrome (multisystemic); characterized by progressive cone-rod dystrophy leading to blindness; sensorineural hearing loss; childhood obesity associated with hyperinsulinemia; and type 2 diabetes mellitus; Dilated cardiomyopathy occurs in approximately 70% of patients during infancy or adolescence; Renal failure, pulmonary, hepatic, and urologic dysfunction are often observed; and systemic fibrosis develops with age MIM# 203800

Publications

Created: 5 Dec 2022, 10:20 a.m.
Last Modified: 5 Dec 2022, 10:20 a.m.
Panel version: 0.5079

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Green
Genetic Health Queensland

Phenotypes

Alstrom syndrome, MIM# 203800

OMIM

606844

Clinvar variants

Variants in ALMS1

Penetrance

None

Publications

Panels with this gene