EVIDENCE CHAPTER 03
Loss of function, missense, inheritance, position, and what each can—and cannot—show.
GENETICS WITHOUT DESTINY
The cleanest genetic comparisons do not tell us who will do well or poorly. They tell us which modifiers, mechanisms, and measurements a stronger study must test.
COMPARABLE LOSS-OF-FUNCTION HISTORIES
Developmental-language vulnerability appears across the loss-of-function histories, while later documentation separates across seizure, cardiac, autonomic, sleep, infection, memory, airway, motor, and menstrual-state questions.
This public page does not cross-link exact private variants. Similar variant types and locations still cannot predict outcomes.
NEARBY IS NOT THE SAME
4 truncating histories cluster in one protein neighborhood, yet they include a severe waking-linked absence and VNS (vagus nerve stimulation) course, adult cardiac and retrieval questions, and a young male record dominated by speech, behavior, macrocephaly, and pseudopapilledema—an optic-disc appearance that can resemble swelling but has another cause.
An identical variant, a nearby variant, and the same broad variant type are not equivalent comparisons.
INHERITANCE · TRANSMISSION, NOT SEVERITY
Familial missense observations in additional histories show why segregation, age, additional findings, and variable expression must be studied together.
To protect privacy, pedigree-specific details are not shown on this public page. Familial transmission supports segregation and modifier research, not causal certainty or a severity forecast.
WHAT TO TEST NEXT
Compare RNA and protein amount, expression from each copy, protein stability and localization, chromatin occupancy and marking, interaction partners, cell type, developmental stage, additional findings, exposures, and each person’s course over time.
A good study must be able to show when an explanation is wrong, not only when it seems to fit.
4 MISSENSE HISTORIES, 4 DISTINCT QUESTIONS
Missense is not “milder loss of function.” Classification, inheritance, residue and domain context, residual function, additional findings, and the person’s course must be examined together.
ADOLESCENT · LIKELY PATHOGENIC MISSENSE
Failure to thrive, pica, cyclic or constipation-linked vomiting, ketosis, low glucose, shutdown, and oral-product intolerance make episode capture more informative than a class-wide severity label.
De novo inheritance is recorded in the available source. The complete laboratory report, residual function, and metabolic or GI differentials remain separate questions.SCHOOL AGE · MISSENSE VUS
Family reports describe absence or spasm-like seizures, repeated abnormal EEG findings, medication-dependent sleep, constipation, oral pain, and gum bleeding.
Inheritance and formal reports remain incomplete. Clinical care follows the observed seizures; variant classification follows genetic evidence.PRESCHOOL · MISSENSE VUS + ADDITIONAL FINDING
Autism and ADHD, heavy sleep or snoring, intermittent abdominal pain, and a reported additional genetic finding occur in one young male history.
Untested parents, the additional finding, age, and incomplete records prevent ASH1L-only attribution.PRESCHOOL · MISSENSE VUS · FAMILY-REPORTED HISTORY
Family-reported allergy testing identified multiple foods, with allergen exposure linked to recurrent bloody diarrhea. Recurrent or allergy-linked rhinorrhea, hypotonia, shirt chewing and other oral sensory seeking, brushing intolerance, low pain response, and temporary ALT/AST elevation after infection create overlapping—but different—GI, allergy, neuromotor, sensory, and recovery questions. Family-reported elastopathy said to be maternally inherited should be considered as a separate family-history factor.
METHODS & TERMS
Methods & Privacy explains the evidence-label definitions, count rules, missing-information framework, and privacy approach used throughout ASH1L.org.
A genetic result tells us where to look. A life course tells us what the gene may actually mean for a person.
— Abbey