Genetics

Question 1

What is the difference between genotype and phenotype?

Answer 1

Genotype:
The genetic makeup of an organicism or more specifically the sequence of a particular gene.

Phenotype:
The constellation of observable traits produced by a particular genotype.

Question 2

Which conditions are associated with NALCN mutations?

Answer 2

1. Infantile Hypotonia with Psychomotor Retardation and characteristic Facies (IHPRF1 and 2):

Genetic Background:
* Individuals heterozygous for UNC-80, UNC-79, and NALCN null mutations develop normally.
* Homozygous deleterious mutations in NALCN and UNC-80 are associated with IHPRF1 and IHPRF2 syndromes, respectively.

Chromosomal Deletions:
* Interstitial deletions of chromosome 13 (13q syndrome) involving NALCN, NALCN-AS1, and FAM155A result in widely varying phenotypes.
* Deletions in chromosome 2 (where UNC-80 resides) are associated with brain anomalies, mental retardation, and dysmorphic features.

2. NALCN Subunit Mutations (IHPRF1 - OMIM #615419):

Pathogenic Variants:
* Homozygous recessive mutations, including nonsense and missense mutations, are associated with IHPRF1.
* Examples include p.Q642X, p.W1287L, p.P908L, p.R1094Q, p.F1427L, p.V1528I, p.V1400F, p.G1303D.

Functional Impact:
* Nonsense mutations lead to mRNA decay or truncated non-functional proteins.
* Missense mutations may result in loss-of-function.

Clinical Presentation:
* Over 43 IHPRF1 patients from 29 families exhibit a range of symptoms with variable severity.

3. UNC-80 Subunit Mutations (IHPRF2 - OMIM #616801):
   Autosomal Recessive Mutations:
   * UNC-80 gene mutations, including nonsense and missense mutations, are associated with IHPRF2.
   * Functional impact varies, with some missense mutations potentially affecting subcomplex stability.

Functional Studies:
* Some truncating mutants are functional but show altered cellular localization.
* Biallelic missense mutations may impact subcomplex stability.

Clinical Presentation:
* Patients with recessive UNC-80 mutations exhibit a variety of symptoms with variable severity.

4. Congenital contractures of the Limbs and Face, Hypotonia, and Developmental Delay (CLIFAHDD - OMIM #616226):

Dominant Mutations:
* CLIFAHDD syndrome results from de novo dominant mutations in NALCN.
* Mutations often located in the pore-forming region of NALCN.

Functional Impact:
* Mutations in CLIFAHDD are suggested to be gain-of-function, causing increased current density.

Functional Studies:
* Mutations such as p.L509S and p.Y578S show increased current density when expressed in neuronal cell lines.

Clinical Presentation:
* CLIFAHDD patients, around 40 reported, exhibit variable symptoms, and most mutations are located in transmembrane helices 5 and 6 of Domains I to IV.

Question 3

How is the NALCN disease pattern?

Answer 3

IHPRF (Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies):
* Patients with heterozygous mutations in UNC-80, UNC-79, and NALCN develop normally.
* Homozygous deleterious mutations in NALCN and UNC-80 are associated with IHPRF1 and IHPRF2 syndromes, respectively.
* Patients with interstitial deletions of chromosome 13, where NALCN localizes, show varying phenotypes.
* Microdeletions in the region of chromosome 2, where UNC-80 resides, are associated with brain anomalies, mental retardation, and dysmorphic features.

IHPRF1 (OMIM #615419) - NALCN Subunit Mutations:
* Patients with recessive homozygous truncating mutations (e.g., p.Q642X) in NALCN exhibit severe developmental disorders.
* Various homozygous nonsense and missense mutations in NALCN are reported, causing loss-of-function.
* More than 43 IHPRF1 patients from 29 families exhibit a range of symptoms with variable severity.

IHPRF2 (OMIM #616801) - UNC-80 Subunit Mutations:
* Autosomal recessive mutations in the UNC-80 gene are associated with IHPRF2.
* Both nonsense and missense mutations in UNC-80 are described, impacting the stability of the UNC-79/UNC-80 subcomplex.
* Patients with recessive UNC-80 mutations exhibit a range of symptoms with variable severity.

5. Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay (CLIFAHDD; OMIM #616226):
   * CLIFAHDD is associated with de novo dominant mutations of NALCN.
   * Up to 40 reported patients exhibit a wide range of symptoms, including congenital contractures, hypotonia, and developmental delay.
   * Mutations often occur in the pore-forming region of NALCN, suggesting a direct impact on gating.

Question 4

How is the symptomatology of IHPRF and CLIFAHDD Syndromes?

Answer 4

Over 100 cases of NALCN/UNC-80-related disorders are reported.

Clinical manifestations include
- severe global developmental delay,
- intellectual disability,
- hypotonia,
- dysmorphic facial features, and - distal arthrogryposis in CLIFAHDD syndrome.

Additional features include:
- central apneas,
- periodic breathing,
- epilepsy,
- hyperkinetic movement disorders,
- ataxia,
- sleep disturbances,
- constipation, and
- dysautonomia.

Question 5

What are SNPs?

Answer 5

SNPs – Single nucleotide Polumorphs - relevant for P2X

Question 6

What is compound heterozygous?

Answer 6

Compound heterozygous:
Two damaged alleles are inherited. Unusual and is only really seen in inbread families

Question 7

Loss/Gain OF have similar symptomatic phenotypes, why?

Answer 7

LOF –> Hyperpolarized –> Needs more depolarization to be excitable –> Less excitable

GOF –> Depolarized –> Desensitived/Inactivated form –> Less excitable