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ASH1L LONGITUDINAL CASE PROFILE
Report transcript + cDNA
Report protein consequencep.Ile629*
Normalized MANE/map notationNM_018489.3:c.1885_1888delinsTAA · NP_060959.2:p.Ile629*
A girl in the 6–10 age group with a pathogenic, reportedly de novo ASH1L variant, a history of global developmental delay, mild intellectual disability, and continued developmental progress. Language and learning remain her main areas of support need.
Chapter 01Overview and genetics
Her mother describes an affectionate girl who seeks company, closeness, and physical contact. She has a strong memory and an especially good sense of direction and spatial navigation.
She now speaks in longer sentences, participates in conversations, and is learning to read and write. She has also made meaningful gains in movement and coordination.
Genetic testing at approximately five years old identified the heterozygous ASH1L variant NM_018489.3:c.1885_1888delinsTAA, p.(Ile629*). The report classified the variant as pathogenic for an autosomal-dominant ASH1L-related neurodevelopmental condition. Testing of both parents reportedly did not identify the variant, supporting that it occurred de novo.
The change replaces four coding nucleotides with the three-nucleotide sequence TAA, creating a premature stop signal at amino acid 629. This small sequence-level deletion-insertion is consistent with the established loss-of-function mechanism of ASH1L-related neurodevelopmental disorder. Its exact effect on RNA and protein has not been measured in her own cells.
Array CGH did not identify a copy-number variant, and Fragile X testing was normal. The clinical information accompanying the genetic evaluation described a developmental lag of more than 24 months, particularly affecting language, social development, and motor development. It also recorded head size within the expected range and no distinctive physical features.
Autism and ADHD were considered before the genetic diagnosis, but her evaluation did not result in either diagnosis. Her mother also recalls that previous blood testing, hearing assessment, and brain imaging did not identify a concern.
After diagnosis, the family received broad information about conditions that have sometimes been described in people with ASH1L variants, including epilepsy, Tourette syndrome, autism, ADHD, obsessive-compulsive disorder, and psychiatric conditions. These were presented as possible associations, not as diagnoses assigned to her.
She initially had difficulty latching. She continued breastfeeding until approximately two years old, maintained her weight, and did not require formula.
Turning, standing, walking, and talking all developed later than expected. She stood at approximately 18 months and walked independently at approximately 19 to 20 months. She did not crawl before walking.
At two years old, she was not yet speaking, which led to a referral for early assessment and support. Her first words began around that age, and two- to three-word phrases emerged at approximately five years old. Her development has continued without any reported loss of previously acquired skills.
She now uses longer, more functional speech, although her sentences may remain incomplete or grammatically incorrect. She has difficulty with:
Repetition and visual support help her understand information. When another person does not understand her, she can sometimes try again using simpler language.
She also frequently repeats questions about familiar daily events. For example, she may ask several times whether there will be school the following day or whether she needs to shower, including immediately after receiving an answer. The reason for this pattern is not yet clear, and it has not been formally assessed.
A previous assessment identified mild intellectual disability and reported an IQ score of 63. As with any single standardized score, this does not capture the full range of her abilities or everyday functioning.
Her school supports include an individualized curriculum, specialized educational and language groups, and weekly speech-language support. She also receives individual speech and educational support outside school.
Her reading and writing skills are emerging but require sustained effort, and she can tire quickly while working on them. Visual information and repetition are especially helpful for her learning.
Her mother reports that she can find change difficult and may experience periods of distress. She also describes her as generally quite fearful.
Repetitive movements may appear when she is frustrated. She also rocked at school at approximately four to five years old, but this behavior later stopped. These observations have not been linked to a specific behavioral or psychiatric diagnosis.
Chapter 03Neurology, sleep, movement, and pain
No epilepsy has been reported. Her mother has not observed staring or disconnection, freezing, unusual eye movements, fainting, tremor, unexplained falls, or episodes that were difficult to interrupt.
She has not had an EEG.
Sleep has long been closely connected with physical proximity. As an infant, she needed prolonged rocking and contact to fall asleep, while her daytime sleep was brief. Co-sleeping or close nighttime contact continued until approximately seven years old.
She now sleeps in her own bedroom, although an adult needs to remain with her until she falls asleep. When sleeping away from home, she does not want to sleep alone. A bright night-light, nighttime awakenings, and occasional sleep talking have also been described.
Her mother has felt that she sleeps fewer hours than expected for her age, but she generally wakes with good energy.
Her mother recalls earlier clumsiness, falls, and difficulty with coordination. Her coordination improved after she began participating in sports, and no concern about muscle tone has been reported.
Her leg pain is now less frequent, although no cause has been identified. No persistent gait difference, walking-related fatigue, consistent asymmetry, joint pain, stiffness, or hypermobility has been reported.
Chapter 04Eating, metabolism, ENT, immune, and skin
Her teeth erupted slightly later than expected but remained within the range her family was told was normal. No current difficulty with chewing, choking, reflux, or vomiting has been reported. She tends to eat quickly.
Her mother has not reported constipation, diarrhea, abdominal pain, abdominal swelling, or food intolerance. She has also described an increased appetite and a strong preference for sweets. She can become distressed when sweets are unavailable.
She previously experienced metabolic acidosis that persisted for several months. It was monitored and treated with sodium bicarbonate and has now resolved completely.
Its underlying cause was not identified, and no relationship between the episode and ASH1L has been established.
A hearing test at approximately two years old was reported as normal. Her mother has not reported recurrent ear infections, middle-ear fluid, hearing loss, chronic nasal congestion, tonsil or adenoid problems, mouth breathing, or recurrent throat infections.
Loud sounds continue to bother her. She occasionally snores when she has a cold or nasal congestion rather than as a persistent pattern.
At approximately five years old, she had severe pneumonia reported to involve several viruses and required about one month of intensive care. Her mother reports that she recovered completely without lasting effects. This was a major isolated illness, and her family has not described a broader pattern of recurrent severe infections.
Seasonal runny nose and ordinary colds have been reported. A small patch of eczema resolved, and mild scalp scaling has also been described. No known allergy or intolerance, poor wound healing, easy bruising, recurrent mouth sores, or recurrent skin infections has been reported.
Chapter 05Puberty, treatment, and the whole-person view
She has precocious puberty and continues to receive monthly injections. Her mother reports that her growth velocity has slowed since treatment began and that her current growth percentile remains within the expected range for her age.
No relationship between her precocious puberty and ASH1L has been established.
She previously received sodium bicarbonate during the now-resolved episode of metabolic acidosis and currently receives monthly injections for precocious puberty. No unexpected medication or anesthesia reaction has been reported.
Her ASH1L diagnosis provides an important explanation for her developmental, language, and learning differences. Other parts of her history—including her severe pneumonia, resolved metabolic acidosis, intermittent leg pain, sleep pattern, appetite changes, and precocious puberty—do not currently have an established relationship to ASH1L.
She continues to gain skills and move forward at her own pace. Her growing conversational language, emerging literacy, improved coordination, strong memory, sense of direction, and affectionate nature are all essential parts of who she is. Understanding her fully means recognizing both the support she needs and the strengths, relationships, and continued growth that shape her life.