p.Ala851Leufs*47 — ASH1L case profile | ASH1L.org

PLEASE WAIT

Loading case profile.

This may take a moment.

Jump to a chapter5 chapters

Chapter 01Who she is, genetics, and developmental course

Who she is

She is an adult woman with an uneven profile and meaningful areas of strength. She recognizes familiar people and well-known actors and singers, has a strong sense of direction, can read public-transport maps, and can work out which bus will take her to different parts of a city. Her mother reports that she can travel around the city independently. She enjoys trips, outings with friends, and a full schedule of activities. These strengths coexist with slow initiation, substantial memory and executive-function difficulties, and a need for continuing support in everyday life.

Genetic finding and diagnosis

Trio exome testing identified a heterozygous ASH1L c.2550delT variant on transcript NM_018489.3. Its protein consequence was written as both p.Ala851LeufsTer47 and p.(Ala851LeuTer47). The single-base deletion shifts the reading frame and introduces a premature stop codon. The variant was classified as pathogenic, arose de novo, and was associated with autosomal-dominant intellectual developmental disorder 52 (ASH1L-related). At the time of the genetic consultation, it had not been described in the scientific literature or genomic databases. The frameshift is expected to disrupt gene function; its position alone does not predict severity or future course.

An earlier 491-gene panel identified a paternally inherited TRIO c.7309G>A, p.Ala2437Thr variant. It was classified as probably benign and was not considered to explain her clinical picture. The genetic referral described psychomotor delay. A neurology history also noted paternal relatives with psychomotor disability.

Early development and school-age change

Her mother reports no early delay in sitting, crawling, walking, or talking. She began walking and talking at about one year. At around age three, she recited poems learned at school, presented onstage during school performances, and remembered her classmates’ names.

Chapter 02Cognition, communication, autonomy, and emotional health

Cognitive and neuropsychological history

Intellectual disability was first diagnosed at around age twelve. A 2012 WISC-III evaluation reported a total IQ of 45, verbal IQ of 44, and performance IQ of 59, interpreted as moderate intellectual disability. Object assembly was a relative strength, with a scaled score of 9 compared with an average scaled score of 3 across the other subtests. The assessment described concrete and rigid thinking, judgment closely tied to immediate perceptual information, literal social understanding, and multiple phobias, especially around medical visits. Cognitive testing recorded IQ scores of 49 in 2011 and 44 in 2018.

Adult neuropsychological testing found a global cognitive index of 40 against a cutoff of 72, an SPM score below the minimum needed to calculate an IQ, and a FAB score of 14 below the stated norm. Most tested domains were impaired, with markedly slow execution and major executive-function difficulty involving abstract reasoning and cognitive flexibility. Attention, visuoconstructive abilities, and long-term memory under interfering conditions were relative areas of preservation, and her reproduction of a complex figure was substantially adequate in form and size.

The adult assessment described reduced initiative, passivity, anhedonia, and severe effects on intellectual function and everyday autonomy. It diagnosed severe intellectual disability and raised, but did not confirm, a possible major neurocognitive disorder with behavioral disturbance and a possible degenerative component. Her mother describes progressive memory worsening since school age, with a more marked decline during the last three to five years. The assessment recommended periodic cognitive follow-up. At times she has declined further cognitive testing because finding the tasks difficult was distressing for her.

A later neurology assessment described severe cognitive impairment related to the de novo pathogenic ASH1L variant, cognitive deterioration, and more recent behavioral manifestations. Psychiatric assessment for possible mood-stabilizing treatment was recommended.