Genetics and dysmorphology

Numerical abnormalities:

• polyploid—additional sets of 23 chromosomes as in triploidy

• aneuploidy—presence or absence of one or more chromosome

• trisomy—presence of three copies of a chromosome

• monosomy—presence of only one member of the chromosome pair

Structural abnormalities

Translocations, most inversions and large (microscopic) deletions, duplications or insertions will be visible on karyotype. Chromosome microarray analysis will detect even small changes in copy number (sub-microscopic deletions and duplications) but will fail to detect other rearrangements, such as translocations and inversions, unless there are associated alterations in copy number of nearby sequences. The recognised types of structural abnormalities ( Figure 5.1 ) include:

• translocation—transfer of material from one chromosome to another

• balanced translocation—transfer of material between chromosomes but no loss of genetic material

• reciprocal translocation—chromosome breaks and exchange of material between chromosomes

• Robertsonian translocation—breaks close to the centromere of acrocentric chromosomes and subsequent fusion with another acrocentric chromosome. This leads to the loss of both short arms of the chromosomes involved but without adverse consequences as the missing regions contain no protein-coding genes

• insertion—insertion of segment into another position in a chromosome

• deletion—loss of part of chromosome

• duplication—duplication of part of a chromosome

• inversion—section of a chromosome rotated by 180° and reinserted

• ring chromosome—chromosome break, with the two ends joining together to form a ring. There is loss of chromosomal material.

Sex chromosome abnormalities

• loss of part or all of one of the sex chromosomes as in Turners syndrome (45X0)

• duplication of one the sex chromosomes as in Klinefelter syndrome (47 XXY)

Genetic sequence variants (point mutations)

• alterations of one or several contiguous nucleotides, usually within a gene and often within the coding sequence or nearby, so that RNA splicing is affected.

These alterations can be complex. The simplest categories are:

• substitutions—replacement of one nucleotide by another

• insertions—addition of one or more nucleotide

• deletions—loss of one or more nucleotide

The brief description of the nucleotide alteration within the coding sequence of a gene is preceded by ‘c.’ (for coding) and then followed by the associated change in the amino acid sequence of the relevant protein product, itself preceded by ‘p.’ (for protein). Thus, the commonest pathogenic variant in the CFTR gene, causing cystic fibrosis in homozygotes and formerly known as ΔF508, is now presented as: c.1521_1523delCTT; p.Phe508Del.

Such alterations in DNA sequence are now classified by their pathogenicity as definitely benign (class 1), probably benign (class 2), of uncertain significance (class 3), probably pathogenic (class 4) or definitely pathogenic (class 5). There are multiple factors to be taken into account in deciding whether or not a variant is pathogenic. This is complex and involves bioinformatic analysis according to national and international standards and comparisons with international reference databases. It may also require a comparison with test results on parents, siblings and other members of the family.

Autosomal dominant conditions

The disorder is expressed completely in the heterozygote individual, and all offspring of an affected person will have a 50% chance of inheriting the mutation, giving rise to vertical transmission in the pedigree. Variable expression and incomplete or age-dependent penetrance can complicate recognition of autosomal dominant inheritance.

Autosomal recessive conditions

The disorder is expressed in the affected homozygote individuals and may arise de novo or be recognised if

there are affected siblings. When both parents are carriers, each of their offspring has a 25% risk of being homozygous affected and a 50% risk of being a heterozygous carrier.

X chromosome linked conditions

These conditions result from mutations in a gene carried on the X chromosome and therefore males are usually affected as they only have one copy of the gene. Female carriers of X-linked conditions are often unaffected but may show some features of the disease, although usually less severely than an affected male.

Features of this X-linked form of inheritance are:

• no male-to-male transmission

• all daughters of an affected male will be carriers

• half of all daughters of a carrier female will be carriers

X chromosome gene disorders are occasionally separated into X-linked recessive, which tend not to manifest significantly in females, and X-linked dominant in which females are commonly affected. In some of these conditions, males may be so severely affected as to die in utero or in early infancy. The distinction between X-linked recessive and X-linked dominant can help in assessing patterns of inheritance in a family, although the random and variable nature of X chromosome inactivation will often blur the distinction.

Mitochondrial mutations

Mitochondrial DNA mutations are transmitted by maternal inheritance and are passed down from mother to child but not from father to child. In most people, all mitochondria contain identical copies of the mitochondrial genome (homoplasmy), but in those with mitochondrial disorders there may be a mix of mitochondria with normal and mutated DNA within each cell (heteroplasmy), especially if the mutation would be lethal if it were present in all copies of the genome (that is, if there were homoplasmy for the mutation).

Imprinting conditions

For most autosomal genes, both alleles are expressed in a cell but, for some, only one allele is expressed and the other is switched off. Whether an allele is expressed or repressed is determined by the sex of the parent contributing that gene and the phenomenon is termed imprinting (see Figure 5.2 ). The terms used are:

• maternally imprinted gene—the maternally derived allele is inactivated

• paternally imprinted gene—the paternally derived allele is inactivated

Down syndrome

Trisomy 21—most arise through nondisjunction

Common phenotypic features

• eyes—up-slanting, epicanthic folds, Brushfield spots, cataracts

• midface hypoplasia, small mouth and jaw

• brachycephaly

• hand abnormalities—single palmar crease, (short broad) hands, clinodactyly

• hypotonia and hypermobility

• intellectual disability common (usually mild-moderate)

• cardiac abnormalities—AVSD most common then VSD then ASD

Antenatal screening is offered to all pregnant women and is outlined in further detail below. Details of management are to be found in Chapter 27 Neurodevelopmental Medicine

Patau syndrome

Trisomy 13

Common phenotypic features include

• cleft lip and palate

• polydactyly

• eye abnormalities—microphthalmia, anophthalmia, coloboma

• cardiac anomalies—VSD, ASD

• CNS defects, including holoprosencephaly and meningomyelocoele

• death usually within the first 12 months

Edward syndrome

Trisomy 18

Common phenotypic features include

• significant defects in brain development

• eye abnormalities—microphthalmia, anophthalmia, coloboma

• cardiac anomalies—VSD, ASD

• characteristic hand position at birth (see Figure 5.3 )

  

• death usually within the first 12 months, but survival has improved over the past few decades