Medical Genetics

The Genetics & Biology of the Distal BP2-BP3 Region

At a Glance

Distal 16p11.2 BP2-BP3 deletion removes SH2B1 and other genes, which can affect appetite, metabolism, brain development, and behavior. Parent testing distinguishes an inherited deletion from a new change, while additional testing may explain unusually severe features.

Understanding the genetics of the Distal BP2-BP3 region is like looking at a specific, 220-kilobase (kb) section of an instruction manual that has been accidentally removed ^[1]^[2]. While this section is small—containing only 9 genes compared to the thousands in your body—the information it holds is vital for how your body manages energy and how the brain develops ^[3]^[1].

The Blueprint: Genes in the BP2-BP3 Region

The distal 16p11.2 region is located between the “breakpoints” labeled BP2 and BP3 ^[1]. Although there are 9 genes in this area, research has focused heavily on one in particular: SH2B1 ^[4]^[5].

SH2B1 (The Energy Manager): This gene acts as a “bridge” or adaptor protein that helps two critical hormones, leptin and insulin, talk to your cells ^[6]^[7].
- Leptin tells your brain when you are full and helps you burn energy ^[8]^[9].
- Insulin helps your body process sugar for fuel ^[6].
- When one copy of the SH2B1 gene is missing, these signals can become muffled. This increases the risk for many people with this deletion to experience hyperphagia (an intense, constant hunger) and develop obesity and insulin resistance early in life ^[10]^[4].
Other Genes: The region also includes candidate genes like LAT, which is studied for its role in the immune system and brain signaling ^[1]^[11]. Because these genes are deleted together, the combined effect can lead to the “spectrum” of symptoms seen in this syndrome ^[12].

Why Parents Need Testing

When a microdeletion is found, doctors usually recommend evaluating both biological parents ^[13]. This is important for two main reasons:

De Novo vs. Inherited: Many cases are de novo, meaning the deletion happened by chance for the first time in the patient ^[13]. However, deletions can also be inherited from a parent ^[13]. If a parent carries the deletion, they have a 50% chance of passing it to each pregnancy.
The “Hidden” Carrier: Because of variable expressivity, a parent can carry the deletion and have almost no symptoms, or perhaps only mild weight or attention issues ^[14]^[2]. Knowing if a parent carries the deletion helps the family understand the risk of it occurring again in future children and helps the parent monitor their own metabolic health ^[14]^[15].

The “Second Hit” Hypothesis

You may notice that some people with this deletion have very mild symptoms, while others have more significant challenges like severe autism or physical differences. To explain unusually severe cases, genetics teams sometimes look for a “second hit” or two-hit model ^[16].

Think of the BP2-BP3 deletion as the “first hit”—a genetic vulnerability. A “second hit” is an additional genetic change elsewhere in the genome that, when combined with the first, makes symptoms more severe ^[17]^[16].

Additional CNVs: Some patients may have a second, unrelated microdeletion or duplication in a different part of their DNA ^[17].
Specific Modifiers: For example, in broader 16p11.2 studies, a second change in a gene called TBX6 can lead to congenital scoliosis (curvature of the spine), though this is mostly associated with the proximal region ^[18].
Polygenic Background: Everyone has a “background” of thousands of tiny genetic variations inherited from their parents. These variations can either protect you or make you more susceptible to the effects of the BP2-BP3 deletion ^[19]^[20].

A “second hit” is not a routine diagnosis for typical features. If symptoms seem unexpectedly severe, your doctor may suggest further testing, such as Exome Sequencing, as a research or phenotype-dependent consideration to look for these secondary “hits” ^[1]^[21]. Identifying a second hit doesn’t change the first diagnosis, but it can provide a much clearer picture of why a patient is facing specific challenges.

Common questions in this guide

Which genes are involved in a distal BP2-BP3 deletion?

The distal BP2-BP3 region is a small segment of chromosome 16 containing about nine genes. SH2B1 is especially important because it helps cells respond to leptin and insulin, while other deleted genes may contribute to brain, immune, and developmental features.

How can loss of one SH2B1 copy affect health?

SH2B1 helps leptin signal fullness and helps insulin support the use of sugar for energy. When one copy is missing, some people develop intense hunger, obesity, or insulin resistance early in life, although features vary from person to person.

Can a distal 16p11.2 deletion be inherited?

The deletion may occur as a new genetic change in a person or may be inherited from a biological parent. If a parent carries the deletion, there is a 50% chance of passing it to each pregnancy, so parent testing can help clarify recurrence risk.

What does variable expressivity mean for this deletion?

Variable expressivity means that people with the same deletion can have different features and different levels of severity. A parent may carry the deletion with few or mild symptoms, such as weight or attention concerns, while another family member may be more significantly affected.

What is a second hit, and when might exome sequencing be considered?

A second hit is an additional genetic change that may increase or alter the effects of the BP2-BP3 deletion. Clinicians may consider exome sequencing or other testing when features are unexpectedly severe, but this is not a routine test for everyone and does not replace the original diagnosis.

What health monitoring should someone with a distal 16p11.2 deletion discuss?

Because SH2B1 is involved in leptin and insulin signaling, it is reasonable to ask the healthcare team how to monitor metabolic health. The appropriate blood tests and schedule depend on age, symptoms, and medical history, so a genetics or metabolic specialist should tailor the plan.

Get notified when new evidence is published on Distal 16p11.2 microdeletion syndrome.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.

References (21)

1
Evaluation of 100 Dutch cases with 16p11.2 deletion and duplication syndromes; from clinical manifestations towards personalized treatment options.
Vos N, Kleinendorst L, van der Laan L, et al.
European journal of human genetics : EJHG 2024; (32(11)):1387-1401 doi:10.1038/s41431-024-01601-2.
PMID: 38605127
2
The Phenotypic Spectrum of 16p11.2 Recurrent Chromosomal Rearrangements.
Mitrakos AK, Kosma K, Makrythanasis P, Tzetis M
Genes 2024; (15(8)) doi:10.3390/genes15081053.
PMID: 39202413
3
Discordant phenotypes in monozygotic twins with 16p11.2 microdeletions including the SH2B1 gene.
Li L, Huang L, Lin S, et al.
American journal of medical genetics. Part A 2017; (173(8)):2284-2288 doi:10.1002/ajmg.a.38284.
PMID: 28544142
4
Chromosomal deletions on 16p11.2 encompassing SH2B1 are associated with accelerated metabolic disease.
Hanssen R, Auwerx C, Jõeloo M, et al.
Cell reports. Medicine 2023; (4(8)):101155 doi:10.1016/j.xcrm.2023.101155.
PMID: 37586323
5
Genetic and structural variation in the SH2B1 gene in the Belgian population.
Aerts E, Beckers S, Zegers D, et al.
Molecular genetics and metabolism 2015; (115(4)):193-8.
PMID: 26031769
6
Diversity in peptide recognition by the SH2 domain of SH2B1.
McKercher MA, Guan X, Tan Z, Wuttke DS
Proteins 2018; (86(2)):164-176 doi:10.1002/prot.25420.
PMID: 29127727
7
Endogenous SH2B1 protein localizes to lamellipodia and filopodia: platinum replica electron-microscopy study.
Diakonova M, Carter-Su C, Svitkina T
microPublication biology 2025; (2025()) doi:10.17912/micropub.biology.001451.
PMID: 39897164
8
Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease.
Jiang L, Su H, Wu X, et al.
Nature communications 2020; (11(1)):1517 doi:10.1038/s41467-020-15328-3.
PMID: 32251290
9
SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus→Dorsal Raphe Nucleus Neurocircuit.
Li Y, Kim MH, Jiang L, et al.
Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2024; (11(31)):e2400437 doi:10.1002/advs.202400437.
PMID: 38885417
10
Genetic Obesity in Children: Overview of Possible Diagnoses with a Focus on SH2B1 Deletion.
Giannopoulou EZ, Zorn S, Schirmer M, et al.
Hormone research in paediatrics 2022; (95(2)):137-148 doi:10.1159/000520402.
PMID: 34689140
11
The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs.
Loviglio MN, Arbogast T, Jønch AE, et al.
American journal of human genetics 2017; (101(4)):564-577 doi:10.1016/j.ajhg.2017.08.016.
PMID: 28965845
12
Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes.
Loviglio MN, Leleu M, Männik K, et al.
Molecular psychiatry 2017; (22(6)):836-849 doi:10.1038/mp.2016.84.
PMID: 27240531
13
[Prenatal ultrasound and genetic characteristics of 60 fetuses with 16p11.2 microdeletion].
Pan L, Wu J, Duan S, et al.
Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 2026; (51(4)):737-743 doi:10.11817/j.issn.1672-7347.2026.260007.
PMID: 42394496
14
The Phenotypic variability of 16p11.2 distal BP2-BP3 deletion in a transgenerational family and in neurodevelopmentally ascertained samples.
Woodbury-Smith M, D'Abate L, Stavropoulos DJ, et al.
Journal of medical genetics 2023; (60(12)):1153-1160 doi:10.1136/jmg-2022-108818.
PMID: 37290907
15
Contrasting outcomes of 16p11.2 microdeletion and microduplication in prenatal diagnosis: phenotypic variability and genetic counseling strategies.
Guo Q, Zhang L, Zuo Y, et al.
Psychiatric genetics 2026; (36(3)):151-155 doi:10.1097/YPG.0000000000000421.
PMID: 42583927
16
Evaluating heterogeneity in ASD symptomatology, cognitive ability, and adaptive functioning among 16p11.2 CNV carriers.
Hudac CM, Bove J, Barber S, et al.
Autism research : official journal of the International Society for Autism Research 2020; (13(8)):1300-1310 doi:10.1002/aur.2332.
PMID: 32597026
17
Maternal Modifiers and Parent-of-Origin Bias of the Autism-Associated 16p11.2 CNV.
Duyzend MH, Nuttle X, Coe BP, et al.
American journal of human genetics 2016; (98(1)):45-57.
PMID: 26749307
18
TBX6 null variants and a common hypomorphic allele in congenital scoliosis.
Wu N, Ming X, Xiao J, et al.
The New England journal of medicine 2015; (372(4)):341-50 doi:10.1056/NEJMoa1406829.
PMID: 25564734
19
Combinatorial effects of gene dosage, polygenic background and environment on complex traits.
Sacks MF, Klein M, Bigdeli TB, et al.
medRxiv : the preprint server for health sciences 2026; doi:10.64898/2026.04.30.26352063.
PMID: 42094142
20
Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p.
Weiner DJ, Ling E, Erdin S, et al.
Nature genetics 2022; (54(11)):1630-1639 doi:10.1038/s41588-022-01203-y.
PMID: 36280734
21
Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants.
Pizzo L, Jensen M, Polyak A, et al.
Genetics in medicine : official journal of the American College of Medical Genetics 2019; (21(4)):816-825 doi:10.1038/s41436-018-0266-3.
PMID: 30190612

This page explains the genetics and inheritance of distal 16p11.2 microdeletion syndrome for informational purposes only and does not constitute medical advice. It cannot predict an individual’s symptoms; discuss testing and health monitoring with a genetics professional.