제12장 유전병 분석 및 상담

* 유전상담은 상담자와 유전질환에 대한 정보를 교환하고 및 충고를 하는 것

* 역사, 가계도작성, 조사, 진단, 상담, 추적 등을 포함

12-1 역사와 가계도 작성

- proband : 유전병이 걸려서 유전상담의 원인을 제공하는 자

- proband의 병력 조사

- 가계도 조사 및 작성 : 세대-로마자, 개인-아라비아 숫자

- 가계도작성 기호(Fig.12.1)

12-2 임상적 검사

- proband를 철저히 검사: 기형 검사 철저히 한다(Table12.1, Fig 12.3)

- 신체지수의 범위를 %로 표시

- 지문 pattern 검사(Table 12.3, Fig.12.4)

- 기형이 다수 발견되면 증후군으로 분류하여 증후군을 찾아야 함

12-3 진단의 확인

- 병력 및 신체검사에 추가적으로 염색체 및 DNA 검사가 필요

- 염색체성이상 질환: 염색체 검사

- 단일 유전자성 질환: DNA 검사, 생화학적 검사(Table 12.4)

- 염색체 검사 혹은 DNA 검사가 필요한 증상(Table 12.5)

12-4 상담

- 상담자에 맞는 수준의 설명

- 임상적 특징, 합병증, 병력, 예후, 치료 및 관리법, 재발률(일반적 재발률과 비교)(Table 12.6).

- 고재발률:1/10 이상, 저재발률: 1/20 이하

- 유전에 관한 잘못된 지식(Table 12.7)

- 자식을 보는 것에 대한 상담. 재발률이 낮으면, 태아의 염색체 혹은 DNA 검사로 위험을 줄일 수 있음을 일러줌

- 상담자가 결정을 하도록 함

12-5 상담시 고려사항

12-5-1 염색체 이상

- 아이가 정상적 염색체 수 이상이면, 부모의 염색체 검사 불요

- 아이가 중복 결손이 있으면 부모 염색체 검사 필요

- 부모가 균형전좌이면, 다른 가족 구성원도 검사

12-5-2 상염색체성 우성유전

- 유전병에 따른 침투도 고려

- 발현도 다양성 고려

- 발병 연령 고려

- DNA 검사(Fig 12.6)

12-5-3 상염색체성 열성유전

- 부모가 보인자: 자녀가 질병일 확률 1/4

- 보인자일 확률 계산(Fig. 12.7)

- DNA 검사 적용의 예(Fig. 12.8)

12-5-4 성염색체성 열성유전(Fig.12.9)

- obligate carrier(확실한 보인자)

- non-obligate carrier(보인자인지 아닌지 확실치 않는 여자): Bayes' theorem 적용

- 간접적 DNA 분석(Fig. 12.10)

- 보인자인 여성을 상담 하려면 가끔 전 가족을 조사할 필요가 있다.

12-5-5 다인자성 질환

- 경험적 재발률 이용

- 소속 집단에서 관찰된  재발률만 적용

12-5-6 불임

- 1/10 couples

- 염색체 검사로 균형적 구조 재배열 과 Klinefelter syndrome 이 아닌지 확인

12-5-7 유산

- 1/6 pregnancies

- 3회 이상 3개월 이내 유산하면, 산부인과적 검사, 호르몬 기능장애, anti-phospholipid antibody 검사, 염색체 검사를 실시(3-5% 염색체 재배열이 원인)

Women who are dealing with infertility, particularly recurrent miscarriages, are likely to undergo testing for antiphospholipid antibodies. Antiphospholipid antibodies (APA) are proteins naturally produced by your body but that mistake your cells for invaders. When APA attack, they bind to a cell’s membrane, making it sticky. This causes improper blood flow and can contribute to the formation of blood clots (thrombosis) as well as other health issues.

Why Test for It?

Individuals who have APA are usually diagnosed with antiphospholipid syndrome (APS). Though not necessarily the cause, APS is commonly found in women who have suffered repeat miscarriage. If no explanation has been found for your fertility issues, receiving an APA test can help pinpoint the problem, thereby allowing you to receive the proper infertility treatment.

However, it is not just people with fertility problems that have APA. Between 2% and 15% of the healthy population have APA in their system, they just don’t know it. This is because their APA levels are so low, they fail to cause any significant health problems. Only in individuals with high APA levels are health issues likely to materialize. Other people that may have high levels of APA include those with lupus, migraine sufferers and people diagnosed with deep vein thrombosis.

Getting Tested

Since there are actually 21 different types of APA, the antiphospholipid antibody test will screen for the various APA. However, it is possible to test for specific APA if your health care provider feels it is necessary. To determine whether you have APA in your system, a sample of your blood will be taken and sent off to a lab for analysis.

The amount of APA in your blood will be measured in titers. Titers refer to the amount of blood that can be diluted until no more antibodies are present in it. Your results can come back as normal, meaning that you have no or very low amounts of APA in your system; borderline, which implies that your blood contains an abnormal amount of APA; and high, meaning that you have too many APA in your blood. A high level normally measures between 1:100 and 1:400.

Receiving Treatment

Women that are found to have high levels of APA will likely request treatment in order to thin out their blood thereby reducing their risk of blood clots, recurrent miscarriage, pregnancy complications (such as pre-eclampsia) and heart attack. Treatment for APS is quite simple: daily administration of low-dose aspirin or an anti-coagulant is typically prescribed.

12-5-8 사산

- 5/1000 babies

- 50% 는 원인불명

- 원인불명의 경우: 재발률은 7%

12-5-9 주산기 사망(선천성 기형동반)(임신20주-분만 28일 사이)

- 7/1000 birth

- 병인은 다양

- 염색체분석, 생검, 방사선 촬영

- 이상의 검사에서 정상이면 재발률은 (집단 발병률에 추가하여) 2-5%

12-5-10 성분화 이상

- 성분화 이상에 여러 요인이 작용

- 3가지 분류: 생식기 이상, 여성 무사춘기, 남성 무사춘기(Table 12.9)

- 호르몬 검사, 염색체 검사 필요

- 유아 생식기 이상일 경우는 성 부여 및 선천성부신과형성일 경우 진단 및 탈염증세 치료가 급선무

12-5-11 유아 급사 증후군

- 2/1000 babies

- 2-6 months

- 형제간 재발률 4-7배

12-5-12 정신지체

- IQ 50 이하

- 신생아 중 1%

- 학생 중 0.3-0.4%(유아기 사망)

- 75%는 원인 알 수 있음(Table 12.10)

- trisomy 21 이 대부분

- 그 외 염색체 이상 2%

- 그 외 240여가지의 단일유전자 이상

- 우성유전 중 가장 흔한 것: tuberous sclerosis(결절성뇌경화증)

Tuberous sclerosis is a rare genetic disease that causes noncancerous tumors to grow in the brain and other organs. Symptoms vary depending on the location of the tumors. Common symptoms include

Skin problems, such as light patches and thickened skin

Seizures

Behavior problems

Learning disabilities

Mental retardation

Kidney problems

Some people have signs of tuberous sclerosis at birth. In others it can take time for the symptoms to develop. In some people the disease is mild, while in others it causes severe disabilities. In rare cases, tumors in vital organs or other symptoms can be life-threatening.

Tuberous sclerosis has no cure, but treatments can help symptoms. Options include medicines, educational and occupational therapy, dermabrasion, and surgery.

출처: http://www.nlm.nih.gov/medlineplus/tuberoussclerosis.html

- 열성유전: PKU, cerebral degenerative disorders, microcephaly 가 대부분

Autosomal recessive primary microcephaly

What is MCPH?

Autosomal recessive primary microcephaly (often shortened to MCPH, which stands for "microcephaly primary hereditary") is a condition in which infants are born with a very small head and a small brain. The term "microcephaly" comes from the Greek words for "small head."

Infants with MCPH have an unusually small head circumference compared to other infants of the same sex and age. Head circumference is the distance around the widest part of the head, measured by placing a measuring tape above the eyebrows and ears and around the back of the head. Affected infants' brain volume is also smaller than usual, although they usually do not have any major abnormalities in the structure of the brain. The head and brain grow throughout childhood and adolescence, but they continue to be much smaller than normal.

MCPH causes intellectual disability, which is typically mild to moderate and does not worsen with age. Most affected individuals have delayed speech and language skills. Motor skills, such as sitting, standing, and walking, may also be mildly delayed.

People with MCPH usually have few or no other features associated with the condition. Some have a narrow, sloping forehead; mild seizures; problems with attention or behavior; or short stature compared to others in their family. The condition typically does not affect any other major organ systems or cause other health problems.

How common is MCPH?

The prevalence of all forms of microcephaly that are present from birth (primary microcephaly) ranges from 1 in 30,000 to 1 in 250,000 newborns worldwide. About 200 families with MCPH have been reported in the medical literature. This condition is more common in several specific populations, such as in northern Pakistan, where it affects an estimated 1 in 10,000 newborns.

What genes are related to MCPH?

MCPH can result from mutations in at least seven genes. Mutations in the ASPM gene are the most common cause of the disorder, accounting for about half of all cases.

The genes associated with MCPH play important roles in early brain development, particularly in determining brain size. Studies suggest that the proteins produced from many of these genes help regulate cell division in the developing brain.

Mutations in any of the genes associated with MCPH impair early brain development. As a result, affected infants have fewer nerve cells (neurons) than normal and are born with an unusually small brain. The reduced brain size underlies the small head size, intellectual disability, and developmental delays seen in many affected individuals.

Read more about the ASPM gene.

See a list of genes associated with MCPH.

How do people inherit MCPH?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of MCPH?

These resources address the diagnosis or management of MCPH and may include treatment providers.

Gene Review: Primary Autosomal Recessive Microcephaly

Gene Tests: Primary Autosomal Recessive Microcephaly and Microcephalic Dwarfism Multi-Gene Panels

Gene Tests: Primary Autosomal Recessive Microcephaly Type 1

Gene Tests: Primary Autosomal Recessive Microcephaly Type 2

Gene Tests: Primary Autosomal Recessive Microcephaly Type 3

Gene Tests: Primary Autosomal Recessive Microcephaly Type 5

Gene Tests: Primary Autosomal Recessive Microcephaly Type 6

Gene Tests: Primary Autosomal Recessive Microcephaly Type 7

Gene Tests: Primary Autosomal Recessive Microcephaly Type 8

Gene Tests: Primary Autosomal Recessive Microcephaly Type 9

MedlinePlus Encyclopedia: Head Circumference

You might also find information on the diagnosis or management of MCPH in Educational resources and Patient support.

General information about the diagnosis and management of genetic conditions is available in the Handbook.

To locate a healthcare provider, see How can I find a genetics professional in my area? in the Handbook.

Where can I find additional information about MCPH?

You may find the following resources about MCPH helpful. These materials are written for the general public.

MedlinePlus - Health information (4 links)

Additional NIH Resources - National Institutes of Health

National Institute of Neurological Disorders and Stroke: Microcephaly

Educational resources - Information pages (5 links)

Patient support - For patients and families (2 links)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

Gene Reviews - Clinical summary

Gene Tests - Genetic tests ordered by healthcare professionals (9 links)

ClinicalTrials.gov - Linking patients to medical research

PubMed - Recent literature

OMIM - Genetic disorder catalog (7 links)

What other names do people use for MCPH?

microcephaly primary hereditary

primary autosomal recessive microcephaly

true microcephaly

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines and How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about MCPH?

Ask the Genetic and Rare Diseases Information Center.

Where can I find general information about genetic conditions?

The Handbook provides basic information about genetics in clear language.

What does it mean if a disorder seems to run in my family?

What are the different ways in which a genetic condition can be inherited?

If a genetic disorder runs in my family, what are the chances that my children will have the condition?

Why are some genetic conditions more common in particular ethnic groups?

These links provide additional genetics resources that may be useful.

Genetics and health

Resources for Patients and Families

Resources for Health Professionals

What glossary definitions help with understanding MCPH?

autosomal ; autosomal recessive ; cell ; cell division ; centrosome ; chromosome ; developmental delay ; gene ; microcephaly ; motor ; motor skill ; mutation ; nerve cell ; neuron ; population ; prevalence ; protein ; recessive ; seizure ; short stature ; sign ; stature ; symptom ; syndrome

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

See also Understanding Medical Terminology.

References (7 links)

출처: http://ghr.nlm.nih.gov/condition/autosomal-recessive-primary-microcephaly

- X-linked: fragile X syndrome

- mild mental hadicap(IQ 50-70): 0.4% of school children, 반은 원인 알 수 있음(주산기 질식, 태아 알콜 증후군, 신경섬유증 1형, 47XXY)

12-5-13 선천성 벙어리

- 1/1000 children, 그 중 반은 유전적 원인(Table 12.11)

- genetic heterogeneity 가 있다 (열성,우성, X-연관)

- 감염등 환경적 원인이 없을 때, 재발률은 1/6

- 이 숫자는 재발률이 낮은 상염색체성 우성유전과 상염색체성 열성유전(재발률1/4)을 임상적으로 구분할 수 없기 때문에 계산된 값이다.

- 두 번째 아이도 벙어리이면, 재발률은 1/4로 조정됨

- 양친 중 한사람이 선천성 벙어리일 때(가족 역사는 정상임), 첫 아이가 벙어리일 경험적 재발률은 1/20.

- 첫 아이가 벙어리이면, 재발률은 1/2 (우성유전)

- 양친모두 벙어리이면, 80%의 가족은 모든 아이가 정상. 10%는 일부 아이가 벙어리, 10%는 모두 벙어리(양친이 열성유전)

12-5-14 선천성 백내장(Table 12.12)

- 1/250 babies

- 환자아이의 정상부모: 재발률이 1/10

12-5-15 친족결혼

- 상염색체성 열성유전과 다인자성 유전이 증가

- 친족결혼의 역사가 없는 가족의 경우 삼촌간: 1/20(집단 발생률의 2배), inbred family의 삼촌간:1/11, 근친상간:1/2

12-5-16 단신

- 100 가지 이상의 원인이 있다(Table 12.13)

12-5-17 방사선 혹은 돌연변이원 노출

- 치료용 방사선 : 정원세포 죽임

- 난자: 수정 전후에 방사선에 민감

12-5-18 부친 확인

- multiple VNTR(60개):

선천성 척추 골단 이형성증(spondyloepiphyseal dysplasia congenita)

뮤코다당증(Mucopolysaccharidosis, MPS)은 gIycosaminoglycans (GAGs)의 분해에 필요한 라이소좀 효소(lysomal enzymes)의 결함으로 GAGs의 대사 산물이 세포의 라이소좀내에 축적되어 점차 세포와 조직, 기관의 기능 이상을 초래하고 신체 질환과 정신 발달 지연을 가져오는 질환이다