Medical Genetics

Diagnosis and Genetic Testing: Finding the CA12 Gene

At a Glance

An elevated sweat chloride test shows abnormal salt loss but cannot identify its cause. BESC1 is confirmed by finding disease-causing changes in both copies of CA12, often through targeted testing or whole exome sequencing after CFTR evaluation.

Finding the cause of complex symptoms like elevated sweat chloride and bronchiectasis often begins with a diagnostic odyssey—a long, sometimes frustrating journey of tests and specialist visits. It can be exhausting to be passed from one test to another without a clear answer. Because BESC1 is so rare and its clinical presentation so closely matches those of Cystic Fibrosis (CF), many families spend months or even years searching for the right diagnosis ^[1]^[2].

Understanding how specialists use different tools to separate BESC1 from other conditions can help you navigate this process.

The Sweat Test: Measuring the Result, Not the Cause

The Quantitative Sweat Chloride Test is the standard tool used to screen for CF. It measures the concentration of salt (chloride) in a person’s sweat ^[3].

A Positive Result: In a typical evaluation, a chloride level of 60 mmol/L or higher is considered supportive of a CF diagnosis when combined with clinical symptoms ^[3]^[4].
The BESC1 Connection: Because the CA XII enzyme is essential for proper ion transport in the sweat ducts, impaired function in this gene also causes salt to stay in the sweat ^[1]^[5].

This means a patient with BESC1 will often have an elevated sweat test result ^[1]. The test accurately detects the excess salt, but it cannot differentiate between a CFTR defect and a CA12 defect.

The CFTR Genetic Test: Important Limitations

When a patient has an elevated sweat test and symptoms like a chronic cough or salt loss, the next step is almost always a CFTR genetic panel ^[6]^[7].

The Goal: This test looks for pathogenic variants in the CFTR gene that cause Cystic Fibrosis.
The Confusion: For patients with BESC1, this test often returns negative or identifies only an incidental variant that does not fully explain the disease ^[1].

This is a common point of confusion. A negative CFTR panel makes classic CF less likely, but it does not by itself rule it out. Standard panels can miss rare sequence variants or structural changes. A negative test does not guarantee perfectly functioning CFTR, and your specialist will use clinical context, repeat testing, and potentially advanced functional testing to thoroughly evaluate CF before moving on.

Definitive Diagnosis: Finding the CA12 Gene

A definitive diagnosis of BESC1 can only be made by looking specifically at the CA12 gene ^[1]. Because this condition is so ultra-rare, it is usually not included in standard newborn screening or basic genetic panels.

There are two main ways doctors find these mutations:

Targeted Genetic Testing: If a doctor specifically suspects BESC1, they can order a test that looks only at the CA12 gene or a small panel of genes known to cause “CF-like” symptoms ^[1].
Whole Exome Sequencing (WES): This is a more comprehensive test that examines the protein-coding regions of a person’s DNA ^[2]. WES is often the tool that finally ends the diagnostic odyssey for BESC1 families by identifying biallelic pathogenic or likely pathogenic variants (meaning a disease-causing mutation was inherited from each parent) in the CA12 gene ^[1]^[2]. Finding a “Variant of Uncertain Significance” (VUS) is not enough to confirm the diagnosis.

Inheritance and Genetic Counseling

BESC1 is an autosomal recessive condition, meaning both parents are typically “carriers” of one CA12 variant but do not have the disease themselves. Consulting a Genetic Counselor is highly recommended. They can review your specific genetic report, explain the difference between pathogenic variants and variants of uncertain significance, arrange parental testing (segregation analysis) to confirm inheritance, and discuss testing options for siblings or future family planning.

Why the Specific Diagnosis Matters

Confirming that the molecular cause is the CA12 gene changes the care strategy. While patients with confirmed Cystic Fibrosis may be prescribed CFTR modulators—drugs designed to target the CFTR protein—those medications are not indicated for BESC1, because the primary molecular defect lies in the CA XII enzyme ^[1]. Instead, the team will focus on individualized salt replacement and lung health monitoring ^[2]^[8].

Getting to the bottom of the genetic cause ensures patients receive the appropriate targeted treatments.

Diagnostic Step	Result in BESC1	What it Means
Sweat Chloride Test	Elevated (often >60 mmol/L)	Confirms abnormal sweat composition; prompts further evaluation ^[1].
CFTR Genetic Test	Negative or Inconclusive	Makes classic CF less likely, but does not by itself rule it out ^[1].
CA12 Genetic Test / WES	Pathogenic Biallelic Variants	Definitively confirms BESC1 ^[2].

Common questions in this guide

Can a high sweat chloride result occur when CFTR testing is negative?

Yes. The sweat test measures how much chloride is in sweat, not which gene is causing the abnormal result, so BESC1 can produce a high value that resembles cystic fibrosis. A negative CFTR panel makes classic cystic fibrosis less likely, but rare variants or structural changes may be missed and further evaluation may be needed.

How is BESC1 confirmed genetically?

BESC1 is confirmed by finding pathogenic or likely pathogenic variants in both copies of the CA12 gene. Doctors may use a targeted CA12 test or whole exome sequencing; a variant of uncertain significance alone does not establish the diagnosis.

When is whole exome sequencing useful for suspected BESC1?

Whole exome sequencing examines the protein-coding regions of many genes and can identify CA12 variants when routine testing has not found an explanation. A targeted CA12 test may be appropriate when BESC1 is strongly suspected, while the best choice depends on the clinical findings and previous test results.

What does autosomal recessive inheritance mean for my family?

In BESC1, a person typically inherits one CA12 variant from each parent, while parents who carry one variant usually do not have the condition. A genetic counselor can review the report, arrange testing for parents or siblings, and explain recurrence risks for future pregnancies.

Are cystic fibrosis medicines used to treat BESC1?

CFTR modulators are not indicated for BESC1 because the primary problem involves the CA XII enzyme rather than the CFTR protein. Care is instead individualized and may include salt replacement and monitoring of lung health.

Curated prompts to bring to your next appointment.

1.Could you explain the specific difference between an elevated sweat chloride test and a conclusive genetic test?
2.Since the CFTR testing was negative or inconclusive, what were the limitations of the specific genetic panel used?
3.Has our case been reviewed by a clinical geneticist who can explain the inheritance pattern of these CA12 variants?
4.If we haven't done it yet, is Whole Exome Sequencing (WES) or a targeted CA12 panel the best next step to confirm a diagnosis?
5.Can we speak with a genetic counselor to discuss recurrence risks for future children or testing for other family members?

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References (8)

1
Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease.
Lee M, Vecchio-Pagán B, Sharma N, et al.
Human molecular genetics 2016; (25(10)):1923-1933 doi:10.1093/hmg/ddw065.
PMID: 26911677
2
Case Report: Novel CA12 Homozygous Variant Causing Isolated Hyperchloridrosis in a Chinese Child With Hyponatremia.
Han M, Peng M, Han Z, et al.
Frontiers in pediatrics 2022; (10()):820707 doi:10.3389/fped.2022.820707.
PMID: 35359895
3
Australasian guideline for the performance of sweat chloride testing 3rd edition: to support cystic fibrosis screening, diagnosis and monitoring.
Massie J, McWhinney A, Greed L, et al.
Clinical chemistry and laboratory medicine 2025; (63(10)):1956-1964 doi:10.1515/cclm-2025-0433.
PMID: 40476459
4
Diagnosis of Cystic Fibrosis in Nonscreened Populations.
Sosnay PR, White TB, Farrell PM, et al.
The Journal of pediatrics 2017; (181S()):S52-S57.e2 doi:10.1016/j.jpeds.2016.09.068.
PMID: 28129813
5
Essential role of carbonic anhydrase XII in secretory gland fluid and HCO3 (-) secretion revealed by disease causing human mutation.
Hong JH, Muhammad E, Zheng C, et al.
The Journal of physiology 2015; (593(24)):5299-312 doi:10.1113/JP271378.
PMID: 26486891
6
The diagnosis of cystic fibrosis.
De Boeck K, Vermeulen F, Dupont L
Presse medicale (Paris, France : 1983) 2017; (46(6 Pt 2)):e97-e108 doi:10.1016/j.lpm.2017.04.010.
PMID: 28576637
7
Guidelines for the clinical management and follow-up of infants with inconclusive cystic fibrosis diagnosis through newborn screening.
Sermet-Gaudelus I, Brouard J, Audrézet MP, et al.
Archives de pediatrie : organe officiel de la Societe francaise de pediatrie 2017; (24(12)):e1-e14 doi:10.1016/j.arcped.2017.07.015.
PMID: 29174009
8
Exertional rhabdomyolysis in carbonic anhydrase 12 deficiency.
Avital D, Hershkovitz E, Loewenthal N
Journal of pediatric endocrinology & metabolism : JPEM 2018; (31(6)):697-699 doi:10.1515/jpem-2017-0483.
PMID: 29750650

This page explains BESC1 diagnosis and CA12 testing for educational purposes only; it does not replace medical advice. A clinical geneticist, genetic counselor, and treating specialist can interpret your results and recommend next steps.

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