Clinical Guidance

GPS. Most GPS-associated pathogenic variants cluster in KAT6B exon 18, the last exon, and are predicted to produce truncated proteins associated with a gain-of-function mechanism . Consistent with this hypothesis, pathogenic variants associated with more severe GPS phenotypes are located more proximally in exon 18 and are predicted to result in a more truncated protein. SBBYSS. SBBYS-causing pathogenic variants also occur most frequently in exon 18, but more distally than the GPS-associated variants. Recently, predicted loss-of-function variants in exons 3, 7, 11, and 14-17 were reported to be associated with the SBBYSS phenotype.

Source: GeneReviews — "KAT6B Disorders"

Penetrance

Penetrance appears to be complete since all individuals reported to date who carry a KAT6B pathogenic variant present a phenotype compatible with KAT6B disorders.

Source: GeneReviews — "KAT6B Disorders"

Diagnostic Criteria

KAT6B disorders include genitopatellar syndrome (GPS) and Say-Barber-Biesecker variant of Ohdo syndrome (Say-Barber-Biesecker-Young-Simpson syndrome; SBYSS).

Suggestive Findings

A KAT6B disorder should be suspected in individuals with findings of either GPS or SBBYSS. Genitopatellar syndrome (GPS). While clinical diagnostic criteria have not been defined for genitopatellar syndrome, the authors propose that the following features should raise suspicion for this disorder. Individuals with two major features or one major feature and two minor features are likely to have a KAT6B disorder.

Table 1.

Features Suggestive of GPS

Category | Features

Major features

| • Genital anomalies (females: clitoromegaly /or hypoplasia of the labia minora or majora; males: cryptorchidism scrotal hypoplasia)

Source: GeneReviews — "KAT6B Disorders"

Differential Diagnosis

Table 4.

Genes of Interest in the Differential Diagnosis of KAT6B Disorders

Gene(s) | Differential Diagnosis Disorder | MOI | Clinical Features of Differential Diagnosis Disorder

Overlapping w/KAT6B Disorders | Not Observed in KAT6B Disorders

CDC45

CDC6

CDT1

GMNN

ORC1

ORC4

ORC6 | Meier-Gorlin syndrome (OMIM PS224690) | AR(AD) | Patellar aplasia or hypoplasia; microcephaly; genital anomalies; contractures | Severe intrauterine postnatal growth restriction; bilateral microtia

ERCC6

ERCC8

| Cerebrooculofacioskeletal syndrome (severe fetal form of Cockayne syndrome) | AR | Arthrogryposis; microcephaly; severe ID | Progressive neurodegenerative disorder; congenital cataracts facial dysmorphism

Source: GeneReviews — "KAT6B Disorders"

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with KAT6B disorders, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Recommended Evaluations Following Initial Diagnosis in Individuals with KAT6B Disorders

Source: GeneReviews — "KAT6B Disorders"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "KAT6B Disorders"

Surveillance Guidelines

Table 7.

Recommended Periodic Surveillance for Individuals with KAT6B Disorders

System/Concern | Evaluation1

Development

| Monitor developmental progress educational needs.

Neurologic

| EEG if clinical suspicion of seizures

Gastrointestinal

| Evaluation of feeding symptoms suggestive of small bowel malrotation

Cardiovascular

| Follow up w/cardiologist if cardiac malformation present

Genitourinary

| Renal function (if hydronephrosis or multiple renal cysts are present)

Hearing

| Monitor for hearing loss.

Ocular

| Evaluate for amblyopia.

Endocrine

| Thyroid function

Musculoskeletal

| Physical medicine, OT/PT assessment of mobility, self-help skills

Follow up for scoliosis if vertebral anomalies are present

OT = occupational therapy; PT = physical therapy

1. Annual or as needed

Source: GeneReviews — "KAT6B Disorders"