Categories: Respiratory system phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 615504 (trait) , 611088 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2022

Cross-species summary: This phene was initially named 'Haplotype with homozygous deficiency, LDHH6' and was renamed after identification of the causal gene and characterisation of the disease. [29/1/2022]

Species-specific name: Haplotype with homozygous deficiency, LDHH6

Species-specific description: Ben Braiek et al. (2021): “By scanning the genome of 19,102 Lacaune sheep using 50 k single nucleotide polymorphism (SNP) phased genotypes and pedigree data, we identified 11 Lacaune deficient homozygous haplotypes (LDHH1 to LDHH11) showing a highly significant deficit of homozygous animals ranging from 79 to 100%. These haplotypes located on chromosomes 3, 4, 13, 17 and 18, spanned regions from 1.2 to 3.0 Mb long with a frequency of heterozygous carriers between 3.7 and 12.1%. When we compared at-risk matings (between carrier rams and daughters of carrier rams) and safe matings, seven of the 11 haplotypes were associated with a significant alteration of two fertility traits, a reduced success of artificial insemination (LDHH1, 2, 8 and 9), and/or an increased stillbirth rate (LDHH3, 6, 8, 9, and 10). The 11 haplotypes were also tested for a putative selective advantage of heterozygous carrier rams based on their daughter yield deviation for six dairy traits (milk, fat and protein yields, fat and protein contents and lactation somatic cell score). LDHH1, 3, 4, 5, 7, 9 and 11 were associated with positive effects on at least one selected dairy trait, in particular milk yield.”

Inheritance: Ben Braiek et al. (2022) "generated at-risk matings (n = 17) between rams and ewes heterozygous for the candidate variant in CCDC65. A total of 16 lambs were born alive with five genotyped as homozygous".

Mapping: Position on ovine genome assembly Oar_v3.1: LDHH6 OAR3: 136.2–137.4 Mb

Molecular basis: Ben Braiek et al. (2022) "analyzed the whole-genome sequences of two Lacaune ram heterozygous carriers of LDHH6. After variant calling and filtering against the variants of 86 non-carrier rams, we have identified a single nucleotide variant (SNV) in the two LDHH6 carriers whose variant allele induced a premature stop codon (p.Glu111*) in the Coiled-Coil Domain Containing 65 (CCDC65) gene".

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Ben Braiek et al. (2022): "CCDC65 is involved in the assembly of the nexin-dynein regulatory complex for the formation of microtubules in ciliated cells. . . . The homozygous lambs suffered from respiratory problems, and four of them died within the first month of life. At necropsy, we observed a broad hepatization of lung lobes possibly induced by infectious pneumonia."

Prevalence: Ben Braiek et al. (2022) reported that the frequency of the c.521T variant in 2,952 French Lacaune Dairy lambs was 7%. They also reported that the "LDHH6 heterozygous carrier frequency observed [in male French Lacaune Dairy lambs considered for genomic selection] is stable in the population between 2017 and 2021" at around 12%. However, the frequency differs substantially between two breeding companies: around 16% in one company and around 6% in the other.

Also, Ben Braiek et al. (2022) reported "the segregation of the CCDC65 c.521G > T variant not only in the Lacaune dairy population but also in the Lacaune meat and Blanche du Massif Central (BMC) populations".

Genetic testing: Ben Braiek et al. (2022): "The management of this lethal recessive allele (frequency of 0.06) through reasoned mating in the Lacaune sheep selection schemes could reduce lamb mortality by 2%."

Breeds: Blanc Du Massif Central (Sheep) (VBO_0001340), Lacaune (Sheep) (VBO_0001474).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: