AP1S2

• Haploinsufficiency score: 3
• Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity

Evidence for haploinsufficiency phenotype

PubMed ID	Description
17186471	Tarpey et al (2006) describes three independent families with X-linked intellectual disability who harbor deleterious variants in AP1S2. Family 445 (previously described by Turner et al. 2003, PMID: 12599187) consists of 5 affected males spanning 4 generations who harbor a p.Q36X (c.160C>T) nonsense variant in exon 2 of the AP1S2 gene. The 8 unaffected obligate carrier females were heterozygous for the p.Q36X variant while 7 neuro-typical males in the family were tested and found to be negative for the p.Q36X variant. Five affected males in the family were not available for testing. Family 502 (previously described by Carpenter et al. 1999, PMID: 10398241) consists of 5 affected males spanning 4 generations who harbor a p.R52X (c.154C>T) nonsense variant in exon 2 of the AP1S2 gene. The 4 unaffected obligate carrier females were heterozygous for the p.R52X variant while 1 neuro-typical male in the family was tested and found to be negative for the p.R52X variant. Family 63 consists of 4 affected males spanning 3 generations who harbor a 4-bp deletion preceding the splice-acceptor site of exon 3 (c.180-5del4fsX64). The 3 unaffected obligate carrier females were heterozygous for the c.180-5del4fsX64 variant while 3 neuro-typical males in the family were tested and found to be negative for the c.180-5del4fsX64 variant. In silico analysis predicted that this deletion reduced the strength of the consensus splice-acceptor site form 94% to 0%. It is likely to cause skipping of exon 3, causing a translational frameshift and inclusion of 3 novel amino acids, with termination at codon 64. In all families, the respective deleterious variant was found to segregate with disease.
17617514	Saillour et al (2007) describes two independent families with X-linked intellectual disability who harbor deleterious variants in AP1S2. The first (French) family consists of 8 affected males spanning 5 generations, three of which were available for testing and harbored a c.255+5G>A splice site variant in intron 3 of the AP1S2 gene. The 4 unaffected obligate carrier females that were available for testing were heterozygous for the c.255+5G>A splice site variant while 2 neuro-typical males in the family were tested and found to be negative for the c.255+5G>A splice site variant. RT-PCR of extracted RNA from one of the affected male patients demonstrated skipping of exon 3 and early termination. It was suggested that skipping of exon 3 would introduce a frameshift, resulting in three novel amino-acids, with premature termination at codon 64. The second (Scottish) family (previously reported by Fried and Sanger. 1973, PMID: 4697849) consists of three affected males, one unaffected obligate carrier, and three unaffected non-carrier females. It was confirmed through DNA analysis that the identified p.Q66X (c.226G>T) nonsense variant in exon 3 of the AP1S2 gene segregated with the X-linked intellectual disability phenotype.
18428203	Borck et al (2008) describes two independent families with X-linked intellectual disability who harbor deleterious variants in AP1S2. Family 1 consists of 3 affected males spanning 3 generations who harbor a p.R52X (c.154C>T) nonsense variant in exon 2 of the AP1S2 gene. The 3 obligate carrier females were heterozygous for the p.R52X variant while 5 neuro-typical males in the family were tested and found to be negative for the p.R52X variant. Family 2 consists of 1 affected male proband harboring a c.289-1G>C splice site variant within the acceptor splice-site of exon 4. This variant was observed to be maternally inherited from a heterozygous clinically unaffected female. RT-PCR of total RNA from the male proband demonstrated a 13-bp deletion predicted to cause a frameshift followed by premature termination (p.V97fsX55).
23756445	Cacciagli et al (2014) describes a family with X-linked intellectual disability who harbors a deleterious variant in the AP1S2 gene. The family consists of 4 affected males spanning 5 generations who harbor a c.426+1G>T splice-site variant in intron 4 of AP1S2. The 3 unaffected obligate carriers available for testing heterozygous for the variant while the 1 neuro-typical male available for testing was negative for the variant. RT-PCR from two affected males, an obligate carrier female, and the unaffected male demonstrated skipping of exon 4 and truncation of exons 3 and 5 (p.V97_E142del).
30383884	Cappuccio et al (2019) re-describes a male proband with X-linked intellectual disability who harbors a c.217C>T (p.Q66X) variant in the AP1S2 gene. The variant was inherited from an unaffected mother. The unaffected brother did not carry this variant, but the unaffected sister did.
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Haploinsufficiency phenotype comments:

Loss of function variants in AP1S2 have been observed in individuals with X-linked intellectual disability, also referred to in the literature/other sources as "Fried type mental retardation" or "Pettigrew syndrome." In addition to intellectual disability, some individuals have been reported to have dysmorphic features, seizures, choreoathetosis, spasticity, and abnormalities on brain MRI.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

• Triplosensitivity score: 0
• Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.