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ASH1L LONGITUDINAL CASE PROFILE
Report transcript + cDNA
Report protein consequencep.Arg2146*
Normalized MANE/map notationNM_018489.3:c.6436C>T · NP_060959.2:p.Arg2146*
A warm, determined preschool-age girl with a highly variable history across development, communication, growth, feeding, bowel function, movement, vision, sensory regulation, spells, sleep, temperature, and medication response
Chapter 01Overview and genetics
She is an affectionate, curious, energetic, funny, and determined preschool-age girl. Her family describes her as often joyful. She enjoys active play, coloring, music, making noise at the piano, dancing, water, lights, and playing with other children. When something captures her interest, she can remain focused and deeply engaged.
She is verbal and social. Clinical visits have captured her playing, coloring, communicating, climbing, and engaging warmly with the people around her. She gets up and dresses herself and wants to participate in ordinary family and school life.
Her functioning is also strikingly variable. At some times she is talkative, coordinated, playful, and easy to engage. At others she may become quieter, harder to reach, unusually floppy or stiff, less coordinated, more sensory-sensitive, or temporarily less able to use skills that are available at baseline. Her teacher has also noticed several visibly different functional states. These shifts can occur within one day as well as across days and may coincide with fatigue, bowel difficulty, illness, sensory overload, or other physical strain. Her history is one of fluctuating access to skills rather than established developmental regression, and no single neurological mechanism has been identified.
Her sociability creates a practical safety concern. A clinician once observed appropriate stranger anxiety, but her family says that she sometimes approaches or readily engages unfamiliar adults with limited caution. She may also climb, jump, or move toward danger without appreciating the risk. Close supervision remains important without treating her friendliness, curiosity, or drive for independence as problems in themselves.
Trio whole-exome sequencing identified a heterozygous, de novo, pathogenic nonsense variant in ASH1L: c.6436C>T, p.(Arg2146*). The variant was not detected in either tested parent, and no secondary findings were reported. The family received the molecular diagnosis when she was approximately 27 months old.
The premature stop is predicted to disrupt normal ASH1L function. That is a molecular prediction; no patient-specific RNA, protein, or other functional study has measured the variant’s effect in her cells. The diagnosis provides an important explanation for her neurodevelopmental history, but it does not prove that every gastrointestinal, endocrine, immune, temperature, medication-response, or other feature described below was caused by ASH1L.
The pregnancy was described as healthy, and she was born full term. Her birth weight was 7 pounds 15.9 ounces, approximately the 78th percentile. She passed newborn hearing screening in both ears.
During labor, her family recalls that her heart rate dipped slightly with contractions and that a nurse used the word “arrhythmia” while preparations for a possible cesarean delivery were underway. The tracing normalized, and her family reports that the post-birth cardiology assessment was reassuring. No fetal or neonatal arrhythmia was diagnosed.
Her early oral pattern was unusual. She never accepted a pacifier, and her suck did not look typical to her family. At times, cheek stimulation, bottle repositioning, or repeated prompting was needed to keep her feeding. A feed could require substantial effort while producing relatively little intake. Her family also recalls rolling-like movement at approximately ten days old, although this was an early family observation rather than a formally assessed milestone.
During roughly the first two months, she passed stool about every 48 hours. At approximately two months, while she had a runny nose and brief cough without fever, her family observed blood-tinged spit-up; telephone triage favored a small nasal-source bleed. Large-volume spit-ups then became prominent, sometimes forceful or projectile and sometimes occurring during burping. Her bowel pattern subsequently changed to frequent loose stools, often five to seven times daily and at times described as foul-smelling, greasy, or floating.
Soft foods remained especially important during approximately her first two years. No aspiration or choking disorder was reported, no dysphagia was diagnosed, and no swallow study was completed. Later genetics visits recorded no current feeding or swallowing difficulty.