Intellectual disability syndromic and non-syndromic
Gene: ALMS1 Green List (high evidence)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
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
Gene: alms1 has been classified as Green List (High Evidence).
Phenotypes for gene: ALMS1 were changed from to Alstrom syndrome, MIM# 203800
Publications for gene: ALMS1 were set to
Mode of inheritance for gene: ALMS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
gene: ALMS1 was added gene: ALMS1 was added to Intellectual disability, syndromic and non-syndromic_GHQ. Sources: Expert Review Green,Genetic Health Queensland Mode of inheritance for gene: ALMS1 was set to Unknown
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.